Substituted Pyrrolo[2,3-D]Pyrimidines As Inhibitors Of Protein Arginine Methyl Transferase 5 (PRMT5)

ABSTRACT

The disclosure is directed to compounds of Formula (I) and Formula (II), Formula (I) and Formula (II) and pharmaceutically acceptable salts or solvates thereof. Pharmaceutical compositions comprising compounds of Formula (I) or Formula (II), as well as methods of their use and preparation, are also described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. ProvisionalApplication No. 62/577,448, filed on Oct. 26, 2017, and to U.S.Provisional Application No. 62/666,724, filed on May 4, 2018. Each ofthese applications is incorporated by reference herein in its entirety.

TECHNICAL FIELD

The disclosure is directed to PRMT5 inhibitors and methods of their use.

BACKGROUND

Protein arginine methylation is a common post-translational modificationthat regulates numerous cellular processes, including genetranscription, mRNA splicing, DNA repair, protein cellular localization,cell fate determination, and signaling. Three types of methyl-argininespecies exist ω NG monomethylarginine (MMA), ωNG, NG assymetricdimethylarginine (ADMA) and ωNG,N′G symmetric dimethylarginine (SDMA).The formation of methylated arginines is catalyzed by the proteinarginine methyl transferases (PRMTs) family of methyltransferases.Currently, there are nine PRMTs annotated in the human genome. Themajority of these enzymes are Type I enzymes (PRMT1, -2, -3, -4, -6, -8)that are capable of mono- and asymmetric dimethylation of arginine, withS-adenosylmethionine (SAM) as the methyl donor. PRMT-5, -7 and -9 areconsidered to be Type II enzymes that catalyze symmetric dimethylationof arginines. Each PRMT species harbors the characteristic motifs ofseven beta strand methyltransferases (Katz et al., 2003), as well asadditional “double E” and “THW” sequence motifs particular to the PRMTsubfamily.

PRMT5 is as a general transcriptional repressor that functions withnumerous transcription factors and repressor complexes, including BRG1and hBRM, BlimpI, and SnaiI. This enzyme, once recruited to a promoter,symmetrically dimethylates H3R8 and H4R3. Importantly, the H4R3 site isa major target for PRMT1 methylation (ADMA) and is generally regarded asa transcriptional activating mark. Thus, both H4R3me2s (repressive; me2sindicates SDMA modification) and H4R3me2a (active; me2a indicates ADMAmodification) marks are produced in vivo. The specificity of PRMT5 forH3R8 and H4R3 can be altered by its interaction with COPR5 and thiscould perhaps play an important role in determining PRMT5 corepressorstatus.

Role of PRMTs in Cancer

Aberrant expression of PRMTs has been identified in human cancers, andPRMTs are considered to be therapeutic targets. Global analysis ofhistone modifications in prostate cancer has shown that thedimethylation of histone H4R3 is positively correlated with increasinggrade, and these changes are predictive of clinical outcome.

PRMT5 levels have been shown to be elevated in a panel of lymphoidcancer cell lines as well as mantle cell lymphoma clinical samples PRMT5interacts with a number of substrates that are involved in a variety ofcellular processes, including RNA processing, signal transduction, andtranscriptional regulation. PRMT5 can directly modify histone H3 and H4,resulting in the repression of gene expression. PRMT5 overexpression canstimulate cell growth and induce transformation by directly repressingtumor suppressor genes. Pal et al., Mol. Cell. Biol. 2003, 7475; Pal etal Mol. Cell. Biol. 2004, 9630; Wang et al. Mol. Cell. Biol. 2008, 6262;Chung et al. J Biol Chem 2013, 5534. In addition to its well-documentedoncogenic functions in transcription and translation, the transcriptionfactor MYC also safeguards proper pre-messenger-RNA splicing as anessential step in lymphomagenesis Koh et al. Nature 2015, 523 7558; Hsuet al. Nature 2015 525, 384.

The discovery of cancer dependencies has the potential to informtherapeutic strategies and to identify putative drug targets.Integrating data from comprehensive genomic profiling of cancer celllines and from functional characterization of cancer cell dependencies,it has been recently discovered that loss of the enzymemethylthioadenosine phosphorylase (MTAP) confers a selective dependenceon protein arginine methyl transferase 5 (PRMT5) and its binding partnerWDR77 MTAP is frequently lost due to its proximity to the commonlydeleted tumor suppressor gene, CDKN2A. Cells harboring MTAP deletionspossess increased intracellular concentrations of methylthioadenosine(MTA, the metabolite cleaved by MTAP). Furthermore, MTA specificallyinhibits PRMT5 enzymatic activity. Administration of either MTA or asmall-molecule PRMT5 inhibitor shows a preferential impairment of cellviability for MTAP-null cancer cell lines compared to isogenicMTAP-expressing counterparts. Together, these findings reveal PRMT5 as apotential vulnerability across multiple cancer lineages augmented by acommon “passenger” genomic alteration.

Role of PRMT5 in Hemoglobinopathies

The developmental switch in human globin gene subtype from fetal toadult that begins at birth heralds the onset of the hemoglobinopathies,b-thalassemia and sickle cell disease (SCD). The observation thatincreased adult globin gene expression (in the setting of hereditarypersistence of fetal hemoglobin [HPFH] mutations; significantlyameliorates the clinical severity of thalassemia and SCD has promptedthe search for therapeutic strategies to reverse gamma-globin genesilencing. Central to silencing of the gamma-genes is DNA methylation,which marks critical CpG dinucleotides flanking the gene transcriptionalstart site in adult bone marrow erythroid cells. It has been shown thatthese marks are established at a consequence of recruitment of the DNAmethyltransferase, DNMT3A to the gamma-promoter by the protein argininemethyltransferase PRMT5. Zhao et al. Nat. Struct Mol. Biol. 2009 16, 304PRMT5-mediated methylation of histone H4R3 recruits DNMT3A, couplinghistone and DNA methylation in gene silencing.

PRMT5 induces the repressive histone mark, H4R3me2s, which serves as atemplate for direct binding of DNMT3A, and subsequent DNA methylation.Loss of PRMT5 binding or its enzymatic activity leads to demethylationof the CpG dinucleotides and gene activation. In addition to theH4R3me2s mark and DNA methylation, PRMT5 binding to the gamma-promoter,and its enzymatic activity are essential for assembly of a multiproteincomplex on the gamma-promoter, which induces a range of coordinatedrepressive epigenetic marks. Disruption of this complex leads toreactivation of gamma gene expression. These studies provide the basisfor developing PRMT5 inhibitors as targeted therapies for thalassemiaand SCD.

SUMMARY

The disclosure is directed to compounds of Formula I and Formula II:

-   -   or a pharmaceutically acceptable salt or solvate thereof;        wherein    -   A is N, C—H or C—R⁴ wherein R⁴ is halo or C₁-C₆haloalkyl;    -   R¹ is —C₁-C₆alk-fused aryl, or —C₁-C₆alk-fused heteroaryl    -   R² is halo, —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₁-C₆alk-OH,        —C₁-C₆alk-halo, —C₁-C₆alk-O—C₁-C₆alkyl,        —C₁-C₆alk-O—C₁-C₆alk-aryl, —O—C₁-C₆alkyl, —NR⁵R⁵′,        —NHC(O)NR⁵R⁵′, —NHC(S)NR⁵R⁵′, —NH—O—R⁵, or —NH—NR⁵R⁵′;    -   R⁵ is H, halo, NH₂, or —C₁-C₆alkyl;    -   R⁵ and R⁵′ are each independently, H, C₁-C₆alkyl, or        —C₁-C₆alk-OC₁-C₆alkyl, or R⁵ and R⁵′, together with the atom to        which they are attached, form a C₂-C₆heterocycloalkyl ring; and    -   R⁶ is H or —C₁-C₆alkyl.

Stereoisomers of the compounds of Formula I and Formula II, and thepharmaceutical salts and solvates thereof, are also described. Methodsof using compounds of Formula I and Formula II are described, as well aspharmaceutical compositions including the compounds of Formula I andFormula II.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an ORTEP representation of the compound of Example 11.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The disclosure may be more fully appreciated by reference to thefollowing description, including the following definitions and examples.Certain features of the disclosed compositions and methods which aredescribed herein in the context of separate aspects, may also beprovided in combination in a single aspect. Alternatively, variousfeatures of the disclosed compositions and methods that are, forbrevity, described in the context of a single aspect, may also beprovided separately or in any subcombination.

The term “alkyl,” when used alone or as part of a substituent group,refers to a straight- or branched-chain hydrocarbon group having from 1to 12 carbon atoms (“C₁-C₁₂”), preferably 1 to 6 carbon atoms (“C₁-C₆”),in the group. Examples of alkyl groups include methyl (Me, C₁alkyl),ethyl (Et, C₂alkyl), n-propyl (C₃alkyl), isopropyl (C₃alkyl), butyl(C₄alkyl), isobutyl (C₄alkyl), sec-butyl (C₄alkyl), tert-butyl(C₄alkyl), pentyl (C₅alkyl), isopentyl (C₅)alkyl), tert-pentyl(C₅alkyl), hexyl (C₆alkyl), isohexyl (C₆alkyl), and the like.

The term “alkenyl” when used alone or as part of a substituent grouprefers to a straight- or branched-chain group having from 2 to 12 carbonatoms (“C₂-C₁₂alkenyl”), preferably 2 to 4 carbons atoms(“C₂-C₄alkenyl”), in the group, wherein the group includes at least onecarbon-carbon double bond. Examples of alkenyl groups include vinyl(—CH═CH₂; C₂alkenyl)allyl(—CH₂—CH═CH₂, C₃alkenyl), propenyl (—CH═CHCH₃;C₃alkenyl); isopropenyl (—C(CH₃)═CH₂; C₃alkenyl), butenyl (—CH═CHCH₂CH₃;C₄alkenyl), sec-butenyl (—C(CH₃)═CHCH₃; C₄alkenyl), iso-butenyl(—CH═C(CH₃)₂; C₄alkenyl), 2-butenyl (—CH₂CH═CHCH₃; C₄alkyl), pentenyl(—CH═CHCH₂CH₂CH₃; C₅alkenyl), and the like.

The term “halo” when used alone or as part of a substituent group refersto chloro, fluoro, bromo, or iodo.

The term “haloalkyl” when used alone or as part of a substituent grouprefers to refers to an alkyl group wherein one or more of the hydrogenatoms has been replaced with one or more halogen atoms. Halogen atomsinclude chlorine, fluorine, bromine, and iodine. Examples of haloalkylgroups of the disclosure include, for example, trifluoromethyl (—CF₃),chloromethyl (—CH₂Cl), and the like.

The term “cycloalkyl” when used alone or as part of a substituent grouprefers to cyclic-containing, non-aromatic hydrocarbon groups having from3 to 10 carbon atoms (“C₃-C₁₀”), preferably from 3 to 6 carbon atoms(“C₃-C₆”). Examples of cycloalkyl groups include, for example,cyclopropyl (C₃), cyclobutyl (C₄), cyclopropylmethyl (C₄), cyclopentyl(C₅), cyclohexyl (C₆), 1-methylcyclopropyl (C₄), 2-methylcyclopentyl(C₄), adamantanyl (C₁₀), and the like.

The term “heterocycloalkyl” when used alone or as part of a substituentgroup refers to any three to ten membered monocyclic or bicyclic,saturated ring structure containing at least one heteroatom selectedfrom the group consisting of O, N and S. Where N is a heteroatom in theheterocycloalkyl group, the N may be substituted with H, —C₁-C₃alkyl,C₁-C₃haloalkyl or C₃-C₆cycloalkyl. The heterocycloalkyl group may beattached at any heteroatom or carbon atom of the ring such that theresult is a stable structure. Examples of suitable heterocycloalkylgroups include, but are not limited to, azepanyl, aziridinyl,azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl,piperazinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl,thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl, quinoclidinyl,tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, and the like.

The term “aryl” when used alone or as part of a substituent group refersto a mono- or bicyclic-aromatic hydrocarbon ring structure having 6 or10 carbon atoms in the ring, wherein one or more of the carbon atoms inthe ring is optionally substituted with a halogen atom, a —C₁-C₃ alkylgroup, an amino-substituted —C₁-C₃ alkyl group, a C₁-C₃ haloalkyl group,an amino group (i.e., —NH₂), or a substituted amino group. Preferredaryl groups include phenyl and naphthyl.

The term “fused aryl” when used alone or as part of a substituent grouprefers to a fused-ring bicyclic-group having 6 to 10 carbon atoms,wherein one of the rings has a fully conjugated pi electron system, andthe other ring does not have a fully conjugated pi electron system; andwherein one or more of the carbon atoms is optionally substituted with ahalogen atom, a —C₁-C₃ alkyl group, an amino-substituted —C₁-C₃ alkylgroup, a C₁-C₃haloalkyl group, an amino group (i.e., —NH₂) or asubstituted amino group. In addition, one or more of the carbon atoms ofthe ring that does not have a fully conjugated pi electron system mayalso optionally substituted with a hydroxy group (—OH), a keto group(C═O), or a cyano group (—CN). Halogen atoms include chlorine, fluorine,bromine, and iodine. Amino-substituted —C₁-C₃ alkyl groups include—CH₂—NH₂, —CH₂CH₂—NH₂, and the like. C₁-C₃haloalkyl groups include, forexample, —CF₃, —CH₂CF₃, and the like. Substituted amino groups include,for example, —NH—C(O)—NH₂. Examples of fused aryl groups include.

and the like.

The term “fused heteroaryl” when used alone or as part of a substituentgroup refers to fused-ring bicyclic group including carbon atoms as wellas up to four heteroatoms selected from nitrogen, oxygen, and sulfur,wherein one of the rings has a fully conjugated pi electron system, andthe other ring does not have a fully conjugated pi electron system.Fused heteroaryl rings can include a total of 8, 9, or 10 ring atoms.The heteroatoms may be present in either the ring having a fullyconjugated pi electron system, or in the ring that does not have a fullyconjugated pi electron system, or in both of the rings. The fusedheteroaryl moiety can be unsubstituted, or one or more of the atoms inthe ring can be substituted with a halogen atom; an amino group, asubstituted amino group, including an amino group substituted with a—C₃-C₆ cycloalkyl group or a —C₁-C₆ alkyl group; or a —C₁-C₃ alkylgroup. Halogen atoms include chlorine, fluorine, bromine, and iodine.Examples of fused heteroaryl groups include

and the like.

When a range of carbon atoms is used herein, for example, C₁-C₆, allranges, as well as individual numbers of carbon atoms are encompassed.For example, “C₁-C₃” includes C₁-C₃, C₁-C₂, C₂-C₃, C₁, C₂, and C₃.

The term “C₃-C₆alk” when used alone or as part of a substituent grouprefers to an aliphatic linker having, 1, 2, 3, 4, 5, or 6 carbon atomsand includes, for example, —CH₂—, —CH(CH₃)—, —CH(CH₃)—CH₂—, and—C(CH₃)₂—. The term “—C₆alk-” refers to a bond. In some aspects, theC₁-C₆alk can be substituted with one or more —OH, —NH₂, or halo (e.g.,—F, —Cl, —Br, with —F being preferred) substituents. C₁alk groups, forexample, include:

and the like.

“Pharmaceutically acceptable” means approved or approvable by aregulatory agency of the Federal or a state government or thecorresponding agency in countries other than the United States, or thatis listed in the U.S. Pharmacopoeia or other generally recognizedpharmacopoeia for use in animals, e.g., in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound of thedisclosure that is pharmaceutically acceptable and that possesses thedesired pharmacological activity of the parent compound. In particular,such salts are non-toxic may be inorganic or organic acid addition saltsand base addition salts. Specifically, such salts include: (1) acidaddition salts, formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike, or formed with organic acids such as acetic acid, propionic acid,hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalene sulfonic acid,4-tolueneusulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like, or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion, or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike. Salts further include, by way of example only, sodium, potassium,calcium, magnesium, ammonium, tetraalkylammonium, and the like; and whenthe compound contains a basic functionality, salts of non-toxic organicor inorganic acids, such as hydrochloride, hydrobromide, tartrate,mesylate, acetate, maleate, oxalate and the like.

A “pharmaceutically acceptable excipient” refers to a substance that isnon-toxic, biologically tolerable, and otherwise biologically suitablefor administration to a subject, such as an inert substance, added to apharmacological composition or otherwise used as a vehicle, carrier, ordiluent to facilitate administration of an agent and that is compatibletherewith. Examples of excipients include calcium carbonate, calciumphosphate, various sugars and types of starch, cellulose derivatives,gelatin, vegetable oils, and polyethylene glycols.

A “solvate” refers to a physical association of a compound of Formula Iwith one or more solvent molecules.

“Subject” includes humans. The terms “human,” “patient,” and “subject”are used interchangeably herein.

“Treating” or “treatment” of any disease or disorder refers, in oneembodiment, to ameliorating the disease or disorder (i.e., arresting orreducing the development of the disease or at least one of the clinicalsymptoms thereof). In another embodiment “treating” or “treatment”refers to ameliorating at least one physical parameter, which may not bediscernible by the subject. In yet another embodiment, “treating” or“treatment” refers to modulating the disease or disorder, eitherphysically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both.In yet another embodiment, “treating” or “treatment” refers to delayingthe onset of the disease or disorder.

“Compounds of the present disclosure,” and equivalent expressions, aremeant to embrace compounds of formula I or Formula II as describedherein, as well as their subgenera, which expression includes thestereoisomers (e.g., entaniomers, diastereomers) and constitutionalisomers (e.g., tautomers) of compounds of Formula I or Formula II aswell as the pharmaceutically acceptable salts, where the context sopermits.

As used herein, the term “isotopic variant” refers to a compound thatcontains proportions of isotopes at one or more of the atoms thatconstitute such compound that is greater than natural abundance. Forexample, an “isotopic variant” of a compound can be radiolabeled, thatis, contain one or more radioactive isotopes, or can be labeled withnon-radioactive isotopes such as for example, deuterium (²H or D),carbon-13 (¹³C), nitrogen-15 (¹⁵N), or the like. It will be understoodthat, in a compound where such isotopic substitution is made, thefollowing atoms, where present, may vary, so that for example, anyhydrogen may be ²H/D, any carbon may be ¹³C, or any nitrogen may be ¹⁵N,and that the presence and placement of such atoms may be determinedwithin the skill of the art.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers.” Isomersthat differ in the arrangement of their atoms in space are termed“stereoisomers,” for example, diastereomers, enantiomers, andatropisomers. The compounds of this disclosure may possess one or moreasymmetric centers; such compounds can therefore be produced asindividual (R)- or (S)-stereoisomers at each asymmetric center, or asmixtures thereof. Unless indicated otherwise, the description or namingof a particular compound in the specification and claims is intended toinclude all stereoisomers and mixtures, racemic or otherwise, thereof.Where one chiral center exists in a structure, but no specificstereochemistry is shown for that center, both enantiomers, individuallyor as a mixture of enantiomers, are encompassed by that structure. Wheremore than one chiral center exists in a structure, but no specificstereochemistry is shown for the centers, all enantiomers anddiastereomers, individually or as a mixture, are encompassed by thatstructure. The methods for the determination of stereochemistry and theseparation of stereoisomers are well-known in the art.

The disclosure is directed to compounds of Formula I:

According to the disclosure, A in Formula I is N, C—H, or C—R⁴. In someaspects, A is N, and the compounds of Formula I have the structure 1A.

In other aspects, A is C—H, and the compounds of Formula I have thestructure IB:

In other aspects, A is C—R⁴, and the compounds of Formula I have thestructure IC:

In some aspects, R⁴ in compounds of Formula IC is halo. In otheraspects, R⁴ in compounds of Formula IC is halo or C₃-C₆haloalkyl.

In some embodiments R⁴ is halo, for example, F, Cl, Br, or I. In someembodiments R⁴ is F. In other embodiments, R⁴ is Br. In yet otherembodiments, R⁴ is I.

In some embodiments, R⁴ is C₁-C₆haloalkyl, for example, C₆haloalkyl,C₅haloalkyl, C₄haloalkyl, C₃haloalkyl, C₂haloalkyl, C₁haloalkyl, —CF₃,and the like. In some embodiments, R⁴ is —CF₃.

The disclosure is directed to compounds of Formula II:

According to the disclosure, A in Formula II is N, C—H, or C—R⁴. In someaspects, A is N, and the compounds of Formula II have the structure IIA:

In other aspects, A is C—H, and the compounds of Formula II have thestructure IIB:

In other aspects, A is C—R⁴, and the compounds of Formula II have thestructure IIC:

In some aspects, R⁴ in compounds of Formula IIC is halo. In otheraspects, R⁴ in compounds of Formula IIC is halo or C₁-C₆haloalkyl.

In some embodiments R⁴ is halo, for example, F, Cl, Br, or I. In someembodiments, R⁴ is F. In other embodiments, R⁴ is Br. In yet otherembodiments, R⁴ is I.

In some embodiments, R⁴ is C₁-C₆haloalkyl, for example C₆haloalkyl,C₅haloalkyl, C₄haloalkyl, C₃haloalkyl, C₂haloalkyl, C₁haloalkyl, —CF₃,and the like. In some embodiments, R⁴ is —CF₃.

In some aspects, R⁴ in the compounds of Formula I and Formula II is—C₁-C₆alk-fused aryl, for example, —C₁alk-fused aryl, —C₂alk-fused aryl,—C₃alk-fused aryl, —C₄alk-fused aryl, —C₅alk-fused aryl, —C₆alk-fusedaryl, —CH₂alk-fused aryl, —CH(OH)-fused aryl, —CH(F)-fused aryl,—CN(NH₂)-fused aryl, —CH(Me)-fused aryl, —C(Me)(OH)-fused aryl, and thelike. In some embodiments wherein R¹ is —C₁-C₆alk-fused aryl, the -fusedaryl is bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl. Thus in someembodiments, R¹ is —CH₂-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—CH₂-(7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—CH₂-(7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—CH(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—CH(OH)-(7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—CH(OH)-(7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—CH(F)-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—CH(F)-(7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—CH(F)-(7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—CH(NH₂)-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—CH(NH₂)-(7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—CH(NH₂)-(7,7-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—CH(Me)-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—CH(Me)-(7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—CH(Me)-(7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—C(Me)(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—C(Me)(OH)-(7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl), or—C(Me)(OH)-(7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl).

In other embodiments wherein R¹ is —C₁-C₆alk-fused aryl, the -fused arylis 7-methylbicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),7,7-dimethylbicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-ol-3-yl),(bicyclo[4.2.0]octa-1(6),2,4-trien-7-one-3-yl),7-methylbicyclo[4.2.0]octa-1(6),2,4-trien-7-carbonitrile-3-yl), or2,3-dihydro-1H-inden-5-yl. Thus, in some embodiments, R¹ is—CH₂—(7-methylbicyclo[4.2.0]octa-1(6),2,4-trien-7-ol-3-yl),—CH₂-(7,7-dimethylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl),—CH2-(bicyclo[4.2.0]octa-1(6),2,4-trient-7-ol-3-yl),—CH₂-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-one-3-yl),—CH₂-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile-3-yl),—CH₂-(2,3-dihydro-1H-inden-5-yl),—CH(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—CH(OH)-(7,7-dimethylbicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—CH(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-ol-3-yl),—CH(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-one-3-yl),—CH(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile-3-yl),—CH(OH)-(2,3-dihydro-1H-inden-5-yl),—CH(F)-7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl),—CH(F)-(7,7-dimethylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl),—CH(F)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-ol-3-yl),—CH(F)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-one-3-yl),—CH(F)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile-3-yl),—CH(F)-(2,3-dihydro-1H-inden-5-yl),-CH(NH₂)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl),—CH(NH₂)-(7,7-dimethylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl),—CH(NH₂)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-ol-3-yl),—CH(NH₂)-bicyclo[4.2.0]octa-1(6),2,4-trien-7-one-3-yl),—CH(NH₂)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile-3-yl),—CH(NH₂)-(2,3-dihydro-1H-inden-5-yl),—CH(Me)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—CH(Me)-(7,7-dimethylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl),—CH(Me)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-ol-3-yl),—CH(Me)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-one-3-yl),—CH(Me)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile-3-yl),—CH(Me)-(2,3-dihydro-1H-inden-5-yl),—C(Me)(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl),—C(Me)(OH)-(7,7-dimethylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl),—C(Me)(OH)-bicyclo[4.2.0]octa-1(6),2,4-trien-7-ol-3-yl),—C(Me)(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-one-3-yl),—C(Me)(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile-3-yl),or —C(Me)(OH)-2,3-dihydro-1H-inden-5-yl).

In some aspects, R¹ in the compounds of Formula I and Formula II is—C₁-C₆alk-fused heteroaryl, for example, —C₁alk-fused heteroaryl,—C₂alk-fused heteroaryl, —C₃alk-fused heteroaryl, —C₄alk-fusedheteroaryl, —C₅alk-fused heteroaryl, —C₆alk-fused heteroaryl, —CH₂-fusedheteroaryl, —CH(OH)-fused heteroaryl, —CH(F)-fused heteroaryl,—CH(NH₂)-fused heteroaryl, —CH(Me)-fused heteroaryl, —C(Me)(OH)-fusedheteroaryl, and the like. In some embodiments wherein R¹ is—C₁-C₆alk-fused heteroaryl, the -fused heteroaryl is2,3-dihydrobenzofuran-6-yl. Thus in some embodiments, R¹ is—CH₂-(2,3-dihydrobenzofuran-6-yl), —CH(OH)-(2,3-dihydrobenzofuran-6-yl),—CH(F)-(2,3-dihdyrobenzofuran-6-yl),—CH(NH₂)-(2,3-dihydrobenzofuran-6-yl),—CH(Me)-(2,3-dihydrobenzofuran-6-yl), or—C(Me)(OH)-(2,3-dihydrobenzofuran-6-yl).

In some embodiments wherein R¹ is —C₁-C₆alk-fused heteroaryl, the -fusedheteroaryl is 5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl. Thus in someembodiments, R¹ is —CH₂-(5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl),—CH(OH)-(5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl),—CH(F)-(5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl),—CH(NH₂)-5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl),—CH(Me)-(5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl), or—C(Me)(OH)-(5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl).

In compounds of Formula I and Formula II in the present disclosure, R³is H, halo, —C₁-C₆alkyl, or NH₂. Thus in some embodiments, R³ is H. Inother embodiments, R³ is halo, for example, F, Cl, Br, or I. In otherembodiments, R³ is —C₁-C₆alkyl, for example, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like.Thus, in some embodiments, R³ is methyl (Me). In yet other embodiments,R³ is NH₂. In the most preferred embodiments, R³ is H.

In some aspects, in compounds of Formula I or Formula II in the presentdisclosure, R² is halo, —C₁-C₆alkyl, —C₁-C₆alk-O—C₁-C₆alkyl, —NR⁵R^(5′),—NHCONR⁵R^(5′), NHC(S)NR⁵R^(5′), —NH—O—R⁵, or —NH—NR⁵R^(5′). In otheraspects, R² in the compounds of Formula I or Formula II is halo,—C₁-C₆alkyl, —C₁-C₄alkenyl, —C₁-C₆alk-OH, —C₁-C₆alk-halo,—C₁-C₆alk-O—C₁-C₆alkyl, —C₁-C₆alk-O-C₁-C₆alk-aryl, —O—C₁-C₆alkyl,—NR⁵R^(5′), —NHC(O)NR⁵R^(5′), —NHC(S)NR⁵R^(5′), —NH—O—R⁵, or—NH—NR⁵R^(5′).

In some aspects, R² is halo, for example, chloro, fluoro, bromo, oriodo. In some embodiments, R² is chloro.

In some aspects, R² is —C₁-C₆alkyl, for example, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like. Insome embodiments, R² is methyl. In other embodiments, R² is n-butyl(—CH₂CH₂CH₂CH₃). In yet other embodiments, R² is isopropyl (—CH(CH₃)₂).

In some aspects, R² is —C₂-C₄alkenyl, for example, —C₄alkenyl,—C₃alkenyl, —C₂alkenyl, vinyl, allyl, isopropenyl, and the like. In someembodiments, R² is vinyl (—CH═CH₂). In other embodiments, R² isisopropenyl (—C(CH₃)═CH₂).

In some aspects, R² is —C₁-C₆alk-OH, for example, C₆alk-OH, C₅alk-OH,C₄alk-OH, C₃alk-OH, C₂alk-OH, C₁-OH, —CH₂—OH, —CH₂CH₂—OH, and the like.In some embodiments, R² is —CH₂—OH. In other embodiments, R² is—CH₂CH₂—OH.

In some aspects, R² is —C₁-C₆alk-halo, for example, C₆alk-halo,C₅alk-halo, C₄alk-halo, C₃alk-halo, C₂alk-halo, C₁alk-halo, —CH₂-halo,—CH₂CH₂-halo, and the like. In some embodiments, R² is —CH₂—Cl. In otherembodiments, R² is —CH₂—F.

In some aspects, R² is —C₁-C₆alk-O—C₁-C₆alkyl, for example,—C₁-C₆alk-O—C₁-C₆alkyl, —C₁-C₅alk-O—C₁-C₆alkyl, —C₁-C₄alk-O—C₁-C₆alkyl,—C₁-C₃-O-C₁-C₆alkyl, —C₁-C₂-O—C₁-C₆alkyl, —C₁alk-O—C₁-C₆alkyl,—C₁-C₆alk-O—C₁-C₅alkyl, C₁-C₆alk-O-C₁-C₄alkyl, —C₁-C₆alk-O—C₁-C₃alkyl,—C₁-C₆alk-O—C₁-C₂alkyl, or —C₁-C₆alk-O-C₁alkyl. In some embodiments, R²is —CH₂CH₂—O—CH₃. In other embodiments, R² is —CH₂—O—CH₂CH₃.

In some aspects, R² is —C₁-C₆alk-O—C₁-C₆alk-aryl, for example,—C₁alk-O—C₁alk-aryl, —C₂alk-O—C₁alk-aryl, —C₃alk-O-C₁alk-aryl,—C₄alk-O—C₁alk-aryl, —C₅alk-O—C₁alk-aryl, —C₆alk-O—C₁alk-aryl,—C₁alk-O—C₂alk-aryl, —C₂alk-O—C₂alk-aryl, —C₃alk-O—C₂alk-aryl,—C₄alk-O—C₂alk-aryl, —C₅alk-O—C₂alk-aryl, —C₆alk-O—C₂alk-aryl,—C₁alk-O—C₃alk-aryl, —C₂alk-O—C₃alk-aryl, —C₃alk-O—C₃alk-aryl,—C₄alk-O—C₃alk-aryl, —C₅alk-O—C₃alk-aryl, —C₆alk-O—C₃alk-aryl,—C₁alk-O—C₄alk-aryl, —C₂alk-O—C₄alk-aryl, —C₃alk-O—C₄alk-aryl,—C₄alk-O—C₄alk-aryl, —C₅alk-O—C₄alk-aryl, —C₆alk-O—C₄alk-aryl,—C₁alk-O—C₅alk-aryl, —C₂alk-O—C₅alk-aryl, —C₃alk-O—C₅alk-aryl,—C₄alk-O—C₅alk-aryl, —C₅alk-O—C₅alk-aryl, —C₆alk-O—C₅alk-aryl,—C₁alk-O—C₆alk-aryl, —C₂alk-O—C₆alk-aryl, —C₃alk-O—C₆alk-aryl,—C₄alk-O—C₆alk-aryl, —C₅alk-O—C₆alk-aryl, —C₆alk-O—C₆alk-aryl. In someembodiments, R² is —C₂alk-O—C₁alk-aryl. In some embodiments, R² is—CH₂CH₂—O—CH₂-phenyl.

In some aspects, R² is —O—C₁-C₆alkyl, for example, —O—C₆alkyl,—O—C₆alkyl, —O—C₄alkyl, —O—C₃alkyl, —O—C₂alkyl, —O—C₁alkyl, —O—CH₃,—OCH₂CH₃, and the like. In some embodiments, R² is —O—CH₃.

In some aspects, R² is —NR⁵R^(5′). Thus, in some embodiments where R⁵and R⁵′ are both H, R² is —NH₂. In some embodiments wherein R⁵ and R⁵′are both methyl, R² is —N(CH₃)₂. In embodiments wherein R⁵ is H and R⁵′is methyl, R² is —NH(CH₃).

In some aspects, R² is —NHCONR⁵R^(5′). Thus, in some embodiments whereR⁵ and R⁵′ are both H, R² is —NHCONH₂. In some embodiments wherein R⁵and R⁵′ are both methyl, R² is —NHCON(CH₃)₂. In embodiments wherein R⁵is H and R⁵′ is methyl, R² is —NHCONHCH₃.

In some aspects, R² is NHC(S)NR⁵R^(5′). Thus, in some embodimentswherein R⁵ and R⁵′ are both H, R² is —NHC(S)NH₂. In embodiments whereinR⁵ and R⁵′ are both methyl, R² is —NHC(S)N(CH₃)₂. In embodiments whereinR⁵ is H and R⁵′ is methyl, R² is —NHC(S)NHCH₃.

In some aspects, R² is —NH—O—R⁵. In some embodiments wherein R⁵ isC₁-C₆alkyl, for example, methyl, R² is —NH—OCH₃. In some embodimentswherein R⁵ is C₁-C₆alkyl, for example, ethyl, R² is —NH—OCH₂CH₃. In someembodiments wherein R⁵ is H, R² is —NH—OH.

In some aspects, R² is —NH—NR⁵R^(5′). In some embodiments wherein R⁵ andR⁵′ are both H, R² is —NH—NH₂. In embodiments wherein R⁵ and R⁵′ areboth C₁-C₆alkyl, for example, methyl, R² is —NH—N(CH₃)₂. In embodimentswherein R⁵ is H and R⁵′ is C₁-C₆alkyl, for example, methyl, R² is—NH—NHCH₃.

In some aspects, R² is —NH—O—R⁵ or —NH—NR⁵R^(5′), the compounds ofFormula I and Formula II may exits as tautomers having (E)- or(Z)-geometry at the exocyclic carbon-nitrogen double bond. The compoundsof Formula I and Formula II described and claimed herein are meant toencompass all such tautomers and geometric isomers, and mixturesthereof. The depiction of a particular tautomer or geometric isomer isnot intended to be limiting. For example, when R² is —NH—O—R⁵, compoundsof Formula I may be represented by any of the following equivalentstructure:

Similarly, when R² is —NH—NR⁵R^(5′), compounds of Formula I may berepresented by any of the following equivalent structures:

Similarly, when R² is —NH—O—R⁵, compounds of Formula II may berepresented by any of the following equivalent structures:

Similarly, when R² is —NH—NR⁵R^(5′), compounds of Formula II may berepresented by any of the following equivalent structures:

In compounds of the present disclosure, R⁵ and R⁵′ are eachindependently H, C₁-C₆alkyl (e.g., methyl, ethyl, propyl, isopropyl,butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like), or—C₁-C₆alk-OC₁-C₆alkyl (e.g., C₁-C₆alk-OC₁-C₆alkyl, C₁-C₅alk-OC₁-C₆alkyl,C₁-C₄-OC₁-C₆alkyl, C₁-C₃alk-OC₁-C₆alkyl, C₁-C₂alk-OC₁-C₆alkyl,C₁alk-OC₁-C₆alkyl, C₁-C₆alk-OC₁-C₅alkyl, C₁-C₆alk-OC₁-C₄alkyl,C₁-C₆alk-OC₁-C₃alkyl, C₁-C₆alk-OC₁-C₂alkyl, or C₁-C₆alk-OC₁alkyl).

In some embodiments, R⁵ is H or C₁-C₆alkyl. In some embodiments, R⁵′ isH or C₁-C₆alkyl.

In some embodiments, R⁵ and R⁵′ are each H.

In some embodiments, R⁵ and R⁵′ are each independently C₁-C₆alkyl. Thus,in some embodiments R⁵ is methyl and R⁵′ is methyl.

In some aspects, R⁵ is C₁-C₆alkyl and R⁵′ is H. Thus, in someembodiments, R⁵ is methyl and R⁵′ is H.

In some aspects, R⁵ and R⁵′ are each independently—C₁-C₆alk-OC₁-C₆alkyl.

In some aspects, R⁵ is —C₁-C₆alk-OC₁-C₆alkyl and R⁵′ is H.

In some embodiments of the disclosure, R⁵ and R⁵′, together with theatom to which they are attached, form a C₂-C₆heterocycloalkyl, forexample, azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl,pyrazolidinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl,oxazepanyl, piperazinyl, and the like.

In compounds of the present disclosure, R⁶ is H or C₁-C₆alkyl. In someembodiments, R⁶ is H. In other embodiments, R⁶ is C₁-C₆alkyl, forexample, methyl.

In some aspects, the present disclosure is directed to compounds ofFormula IA-1

-   -   wherein R¹ is —CH(OH)-fused aryl, —C(Me)(OH)-fused aryl,        —CH(OH)-fused heteroaryl, or C(Me)(OH)-fused heteroaryl; and R²        is —NH₂ or —CH₃.

In other embodiments of the compound of Formula IA-1, R¹ is—CH(OH)-fused aryl, or —C(Me)(OH)-fused aryl; and R² is —NH₂ or —CH₃.

In other embodiments of the compound of Formula IA-1, R¹ is—CH(OH)-fused heteroaryl, or C(Me)(OH)-fused heteroaryl, and R² is —NH₂or —CH₃.

In other embodiments of the compound of Formula IA-1, R¹ is—CH(OH)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—CH(OH)7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—CH(OH)-7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl; and R² is—NH₂ or —CH₃.

In some embodiments of the compound of Formula IA-1, R¹ is—C(Me)(OH)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—C(Me)(OH)-7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl, or—C(Me)(OH)-7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl, and R² is—NH₂ is —CH₃.

In other embodiments of the compound of Formula IA-1, R¹ is—CH(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl),—CH(OH)-(7,7-dimethylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl,—CH(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-ol-3-yl),—CH(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—CH(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile-3-yl),or —CH(OH)-(2,3-dihydro-1H-inden-5-yl); and R² is —NH₂ or —CH₃.

In other embodiments of the compound of Formula IA-1, R¹ is—C(Me)(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl),—C(Me)(OH)-(7,7-dimethylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl),—C(Me)(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—C(Me)(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—C(Me)(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile-3-yl),or —C(Me)(OH)-(2,3-dihydro-1H-inden-5-yl), and R² is —NH₂ or —CH₃.

In yet other embodiments of the compound of Formula IA-1, R¹ is—CH(OH)-2,3-dihydrobenzofuran-6-yl, or—(Me)(OH)-2,3-dihdyrobenzofuran-6-yl, and R² is —NH₂ or —CH₃.

In yet other embodiments of the compound of Formula IA-1, R¹ is—CH(OH)-(5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl) or—C(Me)(OH)-(5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl); and R² is —NH₂ or—CH₃.

In some aspects, the present disclosure is direct to compounds ofFormula IA-2

-   wherein R¹ is —CH(OH)-fused aryl, —C(Me)(OH)-fused aryl,    —CH(OH)-fused heteroaryl, or C(Me)(OH)-fused heteroaryl; and R² is    —NH₂ or —CH₃.

In some embodiments of the compound of Formula IA-2, R¹ is —CH(OH)-fusedaryl, or —C(Me)(OH)-fused aryl, and R² is —NH₂ or —CH₃.

In some embodiments of the compound of Formula IA-2, R¹ is —CH(OH)-fusedheteroaryl, or C(Me)(OH)-fused heteroaryl, and R² is —NH₂ or —CH₃.

In some embodiments of the compound of Formula IA-2, R¹ is—CH(OH)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—CH(OH)-7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—CH(OH)-7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl; and R² is—NH₂ or —CH₃.

In other embodiments of the compound of Formula IA-2, R¹ is—C(Me)(OH)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—C(Me)(OH)-7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl, or—C(Me)(OH)-7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl; and R² is—NH₂ or —CH₃.

In other embodiments of the compound of Formula IA-2, R¹ is—CH(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—CH(OH)-(7,7-dimethylbicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—CH(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-ol-3-yl),—CH(OH)-bicyclo[4.2.0]octa-1(6),2,4-trien-7-one-3-yl),CH(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile-3-yl),or —CH(OH)-(2,3-dihydro-1H-inden-5-yl); and R² is —NH₂ is —CH₃.

In other embodiments of the compound of Formula IA-2, R¹ is—C(Me)(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—C(Me)(OH)-(7,7-dimethylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl),—C(Me)(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-8-ol-3-yl),—C(Me)(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-one-3-yl),—C(Me)(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile-3-yl),or —C(Me)(OH)-(2,3-dihydro-1H-inden-5-yl); and R² is —NH₂ or —CH₃.

In yet other embodiments of the compound of Formula IA-2, R¹ is—CH(OH)-2,3-dihydrobenzofuran-6-yl, or—C(Me)(OH)-2,3-dihydrobenzofuran-6-yl; and R² is —NH₂ or —CH₃.

In yet other embodiments of the compound of Formula IA-2, R¹ is—CH(OH)-(5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl) or—C(Me)(OH)-(5,6-dihydro-4-H-cyclopenta[d]thiazol-2-yl), and R² is —NH₂or —CH₃.

In some aspects, the present disclosure is directed to compounds ofFormula IB-1

-   wherein R¹ is —CH(OH)-fused aryl, —C(Me)(OH)-fused aryl,    —CH(OH)-fused heteroaryl, or C(Me)(OH)-fused heteroaryl; and R² is    —C₁-C₆alkyl, —NR⁵R^(5′), —NHCONR⁵R^(5′), or —NH—O—R⁵; and R⁵ and R⁵′    are independently H, C₁-C₆alkyl; or R⁵R^(5′), together with the atom    to which they are attached, for a C₂-C₆heterocycloalkyl.

In some embodiments of the compound of Formula IB-1, R¹ is —CH(OH)-fusedaryl, —C(Me)(OH)-fused aryl; and R² is —C₁-C₆alkyl, —NR⁵R^(5′),—NHCONR⁵R^(5′), or —NH—O—R⁵; and R⁵ and R⁵′ are independently H,C₁-C₆alkyl, or R⁵ and R⁵′, together with the atom to which they areattached, form a C₂-C₆heterocycloalkyl.

In some embodiments of the compound of Formula IB-1, R¹ is —CH(OH)-fusedheteroaryl, or C(Me)OH)-fused heteroaryl; and R² is —C₁-C₆alkyl,—NR⁵R^(5′), —NHCONR⁵R^(5′), or —NH—O—R⁵; and R⁵ and R⁵′ areindependently H, C₁-C₆alkyl, or R⁵R^(5′), together with the atom towhich they are attached, form a C₂-C₆heterocycloalkyl.

In some embodiments of the compound of Formula IB-1, R¹ is —CH(OH)-fusedaryl, —C(Me)(OH)-fused aryl; and R² is halo, —C₁-C₆alkyl, —C₂-C₄alkenyl,—C₁-C₆alk-OH, —C₁-C₆alk-halo, —C₁-C₆alk-O—C₁-C₆alkyl,—C₁-C₆alk-O—C₁-C₆alk-aryl, or —O—C₁-C₆alkyl.

In some embodiments of the compound of Formula IB-1, R¹ is —CH(OH)-fusedheteroaryl, or C(Me)(OH)-fused heteroaryl; and R² is halo, —C₁-C₆alkyl,—C₂-C₄alkenyl, —C₁-C₆alk-OH, —C₁-C₆alk-halo, —C₁-C₆alk-O—C₁-C₆alkyl,—C₁-C₆alk-O—C₁-C₆alk-aryl, or —O—C₁-C₆alkyl.

In some embodiments of the compound of Formula IB-1, R¹ is—CH(OH)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—CH(OH)-7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—CH(OH)-7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl; and R² is—NH₂, —CH₃, —NH—O—CH₃, —NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In some embodiments of the compound of Formula IB-1, R¹ is—CH(OH)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—CH(OH)-(7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—CH(OH)-(7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl); and R² ishalo, —C₁-C₆alkyl, —C₂-C₄alkenyl, —C₁-C₆alk-OH, —C₁-C₆alk-halo,—C₁-C₆alk-O—C₁-C₆alkyl, —C₁-C₆alk-O—C₁-C₆alk-aryl, or —O—C₁-C₆alkyl.

In other embodiments of the compound of Formula IB-1, R¹ is—C(Me)(OH)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—C(Me)(OH)-7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl, or—C(Me)(OH)-7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl, and R² is—NH₂, —CH₃, —NH—O—CH₃, —NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In other embodiments of the compound of Formula IB-1, R¹ is—C(Me)(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—C(Me)(OH)-(7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl), or—C(Me)(OH)-(7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl); and R²is halo, —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₁-C₆alk-OH, —C₁-C₆alk-halo,—C₁-C₆alk-O—C₁-C₆alkyl, —C₁-C₆alk-O—C₁-C₆alk-aryl, or —O—C₁-C₆alkyl.

In other embodiments of the compound of Formula IB-1, R¹ is—CH(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—CH(OH)-(7,7-dimethylbicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—CH(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-ol-3-yl),—CH(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—CH(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile-3-yl),or —CH(OH)-(2,3-dihydro-1H-inden-5-yl); and R² is —NH₂, —CH₃, —NH—O—CH₃,—NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In other embodiments of the compound of Formula IB-1, R¹ is—C(Me)(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl),—C(Me)(OH)-(7,7-dimethylbicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—C(Me)(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-ol-3-yl),—C(Me)(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—C(Me)(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-trien-7-carbonitrile-3-yl),or —C(Me)(OH)-(2,3-dihydro-1H-inden-5-yl); and R² is —NH₂, —CH₃,—NH—O—CH₃, —NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In yet other embodiments of the compound of Formula IB-1, R¹ is—CH(OH)-2,3-dihydrobenzofuran-6-yl, or—C(Me)(OH)-(2,3-dihydrobenzofuran-6-yl; and R² is —NH₂, —CH₃, —NH—O—CH₃,—NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In yet other embodiments of the compound of Formula IB-1, R¹ is—CH(OH)-(5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl) or—C(Me)(OH)-(5,6-dihydro-4H-cyclopenta[d]thiazol-3-yl); and R² is —NH₂,—CH₃, —NH—O—CH₃, —NH—O—CH₂CH₃, —NHCON(CH₂)₃, or

In some aspects, the present disclosure is directed to compounds ofFormula IIB-2

-   wherein R¹ is —CH(OH)-fused aryl, —C(Me)(OH)-fused aryl,    —C(Me)(OH)-fused heteroaryl, or C(Me)(OH)-fused heteroaryl, and R²    is —C₁-C₆alkyl, —NR⁵R^(5′), —NHCONR⁵R⁵′, or —NH—O—R⁵; and R⁵ and R⁵′    are independently H, C₁-C₆alkyl; or R⁵ and R⁵′, together with the    atom to which they are attached, for a C₂-C₆heterocycloalkyl.

In some embodiments of the compound of Formula IB-2, R¹ is —CH(OH)-fusedaryl, or —C(Me)(OH)-fused aryl; and R² is —C₁-C₆alkyl, —NR⁵R^(5′),—NHCONR⁵R^(5′), or —NH—O—R⁵; and R⁵ and R⁵′ are independently H,C₁-C₆alkyl; or R⁵ and R⁵′, together with the atom to which they areattached, form a C₂-C₆heterocycloalkyl.

In some embodiments of the compound of Formula IB-2, R¹ is —CH(OH)-fusedheteroaryl, or C(Me)(OH)-fused heteroaryl; and R² is C₁-C₆alkyl,—NR⁵R^(5′), —NHCONR⁵R^(5′), or —NH—O—R⁵, and R⁵ and R^(5′) areindependently, H, C₁-C₆alkyl; or R⁵ and R^(5′), together with the atomto which they are attached, for a C₂-C₆heterocycloalkyl.

In some embodiments of the compound of Formula IB-2, R¹ is—CH(OH)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—CH(OH)-7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—CH(OH)-7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl; and R² isNH₂, —CH₃, —NH—O—CH₃, —NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In other embodiments of the compound of Formula IB-2, R¹ is—C(Me)(OH)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—C(Me)(OH)-7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl, or—C(Me)(OH)-7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl; and R² is—NH₂, —CH₃, —NH—O—CH₃, —NH—O—CH₂CH₃, —NHCON(CH₂)₃, or

In other embodiments of the compound of Formula IB-2, R¹ is—CH(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—CH(OH)-(7,7-dimethylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl),—CH(OH)-bicyclo[4.2.0]octa-1(6),2,4-trien-7-ol-3-yl),—CH(OH)-bicyclo[4.2.0]octa-1(6),2,4-trien-7-one-3-yl),—C(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-trien-7-carbonitrile-3-yl),or —CH(OH)-(2,3-dihydro-1H-inden-5-yl); and R² is —NH₂, —CH₃, —NH—O—CH₃,—NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In other embodiments of the compound of Formula IB-2, R¹ is—C(Me)(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl),—C(Me)(OH)-(7,7-dimethylbicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—C(Me)(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-ol3-yl),—C(Me)(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—C(Me)(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile-3-yl),or —C(Me)(OH)-(2,3-dihydro-1H-inden-5-yl); and R² is —NH₂, —CH₃,—NH—O—CH₃, —NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In yet other embodiments of the compound of Formula IB-2, R¹ is—CH(OH)-2,3-dihydrobenzofuran-6-yl, or—C(Me)(OH)-2,3-dihydrobenzofuran-6-yl, and R² is —NH₂, —CH₃, —NH—O—CH₃,—NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In yet other embodiments of the compound of Formula IB-2, R¹ is—CH(OH)-(5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl) or—C(Me)(OH)-(5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl); and R² is —NH₂,—CH₃, —NH—O—CH₃, —NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In some aspects, the present disclosure is directed to compounds ofFormula IC-1:

wherein R¹ is —CH(OH)-fused aryl, —C(Me)(OH)-fused aryl, —CH(OH)-fusedheteroaryl, or C(Me)(OH)-fused heteroaryl; and R² is —C₁-C₆alkyl, —NR⁵⁵′, —NH—O—R⁵, and R⁵ and R⁵′ are independently H, C₁-C₆alkyl, R⁵ andR⁵′, together with the atom to which they are attached, form aC₂-C₆heterocycloalkyl.

In some embodiments of the compound of Formula IC-1, R¹ is —CH(OH)-fusedaryl, or —C(Me)(OH)-fused aryl; and R² is —C₁-C₆alkyl, —NR⁵ ⁵′,—NH—O—R⁵, or —NH—O—R⁵; and R⁵ and R⁵′ are independently H, C₁-C₆alkyl,or R⁵ and R⁵′, together with the atom to which they are attached, form aC₂-C₆heterocycloalkyl.

In some embodiments of the compound of Formula IC-1, R¹ is —CH(OH)-fusedheteroaryl, or C(Me)OH-fused heteroaryl; and R² is —C₁-C₆alkyl,—NR⁵R^(5′), —NHCONR⁵R^(5′), or —NH—O—R⁵, and R⁵ and R^(5′) areindependently H, C₁-C₆alkyl; or R⁵ and R^(5′), together with the atom towhich they are attached, form a C₂-C₆heterocycloalkyl.

In some embodiments of the compound of Formula IC-1, R¹ is—CH(OH)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—CH(OH)-7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—CH(OH)-7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl; and R² is—NH₂, —CH₃, —NH—O—CH₃, —NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In other embodiments of the compound of Formula IC-1, R¹ is—C(Me)(OH)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—CH(Me)(OH)-7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl, or—CH(Me)(OH)-7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl; and R²is —NH₂, —CH₃, —NH—O—CH₃, —NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In some embodiments of the compound of Formula IC-1, R¹ is—CH(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—CH(OH)-7,7-dimethylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl,—CH(OH)-bicyclo[4.2.0]octa-1(6),2,4-trien-7-ol-3-y),—CH(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-one-3-yl),—CH(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile-3-yl),or —CH(OH)-(2,3-dihydro-1H-inden-5-yl); and R² is —NH₂, —CH₃, —NH—O—CH₃,—NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In some embodiments of the compound of Formula IC-1, R¹ is—CH(Me)(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—CH(Me)(OH)-(7,7-dimethylbicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—CH(Me)(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-ol-3-yl),—C(Me)(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—C(Me)(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-trien-7-carbonitrile-3-yl), or —(Me)(OH)-(2,3-dihydro-1H-inden-5-yl); and R² is —NH₂, —CH₃,—NH—O—CH₃, —NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In yet other embodiments of the compound of Formula IC-1, R¹ is—CH(OH)-2,3-dihydrobenzofuran-6-yl, or—C(Me)(OH)-2,3-dihydrobenzofuran-6-yl; and R² is —NH₂, —CH₃, —NH—O—CH₃,—NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In yet other embodiments of the compound of Formula IC-1, R¹ is—CH(OH)-5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl) or—C(Me)(OH)-5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl); and R² is —NH₂,—CH₃, —NH—O—CH₃, —NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In some aspects, the present disclosure is directed to compounds ofFormula IC-2:

wherein R¹ is —CH(OH)-fused aryl, —C(Me)(OH)-fused aryl, —CH(OH)-fusedheteroaryl, or C(Me)(OH)-fused heteroaryl; and R² is —C₁-C₆alkyl, —NR⁵⁵′, —NHCONR⁵ ⁵′, or —NH—O—R⁵; and R⁵ and R⁵′ are independently H,C₁-C₆alkyl, R⁵ and R⁵′, together with the atom to which they areattached, form a C₂-C₆heterocycloalkyl.

In some embodiments of the compound of Formula IC-2, R¹ is —CH(OH)-fusedaryl, or —C(Me)(OH)-fused aryl; and R² is —C₁-C₆alkyl, —NR⁵ ⁵′, —NHCONR⁵⁵′, or —NH—O—R⁵; and R⁵ and R⁵′ are independently H, C₁-C₆alkyl; or R⁵and R⁵′, together with the atom to which they are attached, form aC₂-C₆heterocycloalkyl.

In some embodiments of the compound of Formula IC-2, R¹ is —CH(OH)-fusedheteroaryl, or C(Me)(OH)-fused heteroaryl, and R² is —C₁-C₆alkyl, —NR⁵⁵′, —NHCONR⁵ ⁵′, or —NH—O—R⁵; and R⁵ and R⁵′ are independently H,C₁-C₆alkyl; or R⁵ and R⁵′, together with the atom to which they areattached, form a C₂-C₆heterocycloalkyl.

In some embodiments of the compound of Formula IC-2, R¹ is—CH(OH)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—CH(OH)-7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl, or—CH(OH)-7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl; and R² is—NH₂, —CH₃, —NH—O—CH₃, —NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In some embodiments of the compound of Formula IC-2, R¹ is—C(Me)(OH)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—CH(Me)(OH)-(7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl, or—CH(Me)(OH)-7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl, and R²is —NH₂, —CH₃, —NH—O—CH₃, —NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In other embodiments of the compound of Formula IC-2, R¹ is—CH(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl,—CH(OH)-7,7-dimethylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl,—CH(OH)-bicyclo[4.2.0]octa-1(6),2,4-trien-7-ol-3-yl),—CH(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-one-3-yl,—CH(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile-3-yl),or —CH(OH)-(2,3-dihydro-1H-1H-inden-5-yl); and R² is —NH₂, —CH₃,—NH—O—CH₃, —NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In other embodiments of the compound of Formula IC-2, R¹ is—C(Me)(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—CH(Me)(OH)-7,7-methylbicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—CH(Me)(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-ol-3-yl,—CH(Me)(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-one-3-yl,—CH(Me)(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile-3-yl),or —CH(Me)(OH)-2,3-dihydro-1H-inden-5-yl); and R² is —NH₂, —CH₃,—NH—O—CH₃, —NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In yet other embodiments of the compound of Formula IC-2, R¹ is—CH(OH)-2,3-dihydrobenzofuran-6-yl, or—C(Me)(OH)-2,3-dihydrobenzofuran-6-yl, and R² is —NH₂, —CH₃, —NH—O—CH₃,—NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In yet other embodiments of the compound of Formula IC-2, is—C(OH)-(5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl) or—CH(Me)(OH)-(5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl); and R² is —NH₂,—CH₃, —NH—O—CH₃, —NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In some aspects, the present disclosure is directed to compounds ofFormula IIA-1

wherein R¹ is —CH(OH)-fused aryl, —C(Me)(OH)-fused aryl, —CH(OH)-fusedheteroaryl, or C(Me)(OH)-fused heteroaryl; and R² is —NH₂ or —CH₃.

In some embodiments of the compound of Formula IIA-1, R¹ is—CH(OH)-fused aryl, or —C(Me)OH-fused aryl, and R² is —NH₂ or —CH₃.

In some embodiments of the compound of Formula IIA-1, R¹ is—CH(OH)-fused heteroaryl, or —C(Me)OH-fused heteroaryl, and R² is —NH₂or —CH₃.

In some embodiments of the compound of Formula IIA-1, R¹ is—CH(OH)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl, or 13CH(OH)-7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—CH(OH)-7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl; and R² is—NH₂ or —CH₃.

In some embodiments of the compound of Formula IIA-1, R¹ is—CH(Me)(OH)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—CH(Me)(OH)-7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl, or—CH(Me)(OH)-7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl; and R²is —NH₂ or —CH₃.

In other embodiments of the compound of Formula IIA-1, R¹ is—CH(OH)-7-methylbicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—CH(OH)-7,7-dimethylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl),—CH(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-ol-3-yl),—CH(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—CH(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile-3-yl),or —CH(OH)-(2,3-dihydro-1H-inden-5-yl); and R² is —NH₂ or —CH₃.

In other embodiments of the compound of Formula IIA-1, R¹ is—CH(Me)(OH)-7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl,—CH(Me)(OH)-7,7-dimethylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl),—CH(Me)(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-ol-3-yl),—CH(Me)(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-one-3-yl),—CH(Me)(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile-3-yl),or —CH(Me)(OH)-(2,3-dihydro-1H-inden-5-yl); and R² is —NH₂ or —CH₃.

In yet other embodiments of the compound of Formula IIA-1, R¹ is—CH(OH)-2,3-dihydrobenzofuran-6-yl, or—C(Me)OH-2,3-dihydrobenzofuran-6-yl, or—CH(Me)(OH)-2,3-dihydrobenzofuran-6-yl; and R² is —NH₂ or —CH₃.

In yet other embodiments of the compound of Formula IIA-1, R¹ is—CH(OH)-(5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl) or—C(Me)OH-(5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl); and R² is —NH₂ or—CH₃.

In some aspects, the present disclosure is directed to compounds ofFormula IIA-2

wherein R¹ is —CH(OH)-fused aryl, —CH(OH)-fused heteroaryl, or—C(Me)OH-fused heteroaryl; and R² is —NH₂ or —CH₃.

In some embodiments of the compound of Formula IIA-2, R¹ is—CH(OH)-fused aryl, or —C(Me)OH-fused aryl, and R² is —NH₂ or —CH₃.

In some embodiments of the compound of Formula IIA-2, R¹ is—CH(OH)-fused heteroaryl, or —C(Me)OH-fused heteroaryl, and R² is —NH₂or —CH₃.

In some embodiments of the compound of Formula IIA-2, R¹ is—CH(OH)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—CH(OH)-7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—CH(OH)-7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl; and R² is—NH₂ or —CH₃.

In other embodiments of the compound of Formula IIA-2, R¹ is—CH(Me)(OH)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—CH(Me)(OH)-7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl, or—CH(Me)(OH)-7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl; and R²is —NH₂ or —CH₃.

In some embodiments of the compound of Formula IIA-2, R¹ is—CH(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—CH(OH)-7,7-dimethylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl;—CH(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-ol-3-yl),—CH(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-one-3-yl),—CH(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile-3-yl),—CH(OH)-(2,3-dihydro-1H-inden-5-yl), and R² is —NH₂ or —CH₃.

In some embodiments of the compound of Formula IIA-2, R¹ is—CH(Me)(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—CH(Me)(OH)-7,7-dimethylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl;—CH(Me)(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-ol-3-yl),—CH(Me)(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-one-3-yl),—CH(Me)(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile-3-yl),or —CH(Me)(OH)-2,3-dihydro-1H-inden-5-yl); and R² is —NH₂ or —CH₃.

In yet other embodiments of the compound of Formula IIA-2, R¹ is—CH(OH)-(2,3-dihydrobenzofuran-6-yl, or—CH(Me)(OH)-2,3-dihydrobenzofuran-6-yl; and R² is —NH₂ or —CH₃.

In yet other embodiments of the compound of Formula IIA-2, R¹ is—CH(OH)-(5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl or—CH(Me)(OH)-5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl); and R² is —NH₂ or—CH₃.

In some aspects, the present disclosure is directed to compounds ofFormula IIB-1,

wherein R¹ is —CH(OH)-fused aryl, —C(Me)(OH)-fused aryl, —CH(OH)-fusedheteroaryl, or C(Me)(OH)-fused heteroaryl; and R² is —C₁-C₆alkyl, —NR⁵⁵′, —NHCONR⁵ ⁵′, or —NH—O—R⁵; and R⁵ and R⁵′ are independently H,C₁-C₆alkyl, R⁵ and R⁵′, together with the atom to which they areattached, form a C₂-C₆heterocycloalkyl.

In some embodiments of the compound of Formula IIB-1, R¹ is—CH(OH)-fused aryl, —C(Me)(OH)-fused aryl; and R² is —C₁-C₆alkyl, —NR⁵⁵′, —NHCONR⁵ ⁵′, or —NH—O—R⁵; and R⁵ and R⁵′ are independently H,C₁-C₆alkyl; R⁵ and R⁵′, together with the atom to which they areattached, form a C₂-C₆heterocycloalkyl.

In some embodiments of the compound of Formula IIB-1, R¹ is—CH(OH)-fused heteroaryl, —C(Me)(OH)-fused heteroaryl; and R² is—C₁-C₆alkyl, —NR⁵ ⁵′, —NHCONR⁵ ⁵′, or —NH—O—R⁵, and R⁵ and R⁵′ areindependently H, C₁-C₆alkyl; R⁵ and R⁵′, together with the atom to whichthey are attached, form a C₂-C₆heterocycloalkyl.

In some embodiments of the compound of Formula IIB-1, R¹ is—CH(OH)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—C(OH)-7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—CH(OH)-7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl; and R²——NH₂—CH₃, —NH—O—CH₃, —NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In other embodiments of the compound of Formula IIB-1, R¹ is—C(Me)(OH)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—C(Me)(OH)-7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl; or—C(Me)(OH)-7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl, and R² is—NH₂, —CH₃, —NH—O—CH₃, —NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In other embodiments of the compound of Formula IIB-1, R¹ is—CH(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl,—CH(OH)-(7,7-dimethylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl),—CH(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-ol-3-yl),—CH(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-one-3-yl),—CH(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile-3-yl),or —CH(OH)-(2,3-dihydro-1H-inden-5-yl); and R² is —NH₂—, CH₃, —NH—O—CH₃,—NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In other embodiments of the compound of Formula IIB-1, R¹ is—C(Me)(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—C(Me)(OH)-(7,7-dimethylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl),—C(Me)(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-ol-3-yl),—C(Me)(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-one-3-yl),—C(Me)(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile-3-yl),or —C(Me)(OH)-(2,3-dihydro-1H-inden-5-yl); and R² is —NH₂—, CH₃,—NH—O—CH₃, —NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In yet other embodiments of the compound of Formula IIB-1, R¹ is—CH(OH)-(2,3-dihydrobenzofuran-6-yl, or—C(Me)(OH)-2,3-dihydrobenzofuran-6-yl; and R² is —NH₂—, CH₃, —NH—O—CH₃,—NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In yet other embodiments of the compound of Formula IIB-1, R¹ is—CH(OH)-(5,6-dihydro-4H-cyclopenta-[d]thiazol-2-yl) or—C(Me)(OH)-5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl); and R² is —NH₂—,CH₃, —NH—O—CH₃, —NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In some aspects, the present disclosure is directed to compounds ofFormula IIB-2

wherein R¹ is —CH(OH)-fused aryl, —C(Me)(OH)-fused aryl, —CH(OH)-fusedheteroaryl, or C(Me)(OH)-fused heteroaryl; and R² is —C₁-C₆alkyl, —NR⁵⁵′, —NHCONR⁵R⁵′, or —NH—O—R⁵; and R⁵ and R⁵′ are independently H,C₁-C₆alkyl, R⁵ and R⁵′, together with the atom to which they areattached, form a C₂-C₆heterocycloalkyl.

In some embodiments of the compound of Formula IIB-2, R¹ is—CH(OH)-fused aryl, —C(Me)(OH)-fused aryl; and R² is —C₁-C₆alkyl, —NR⁵⁵′, —NHCONR⁵ ⁵′, or —NH—O—R⁵; and R⁵ and R⁵′ are independently H,C₁-C₆alkyl; R⁵ and R⁵′, together with the atom to which they areattached, form a C₂-C₆heterocycloalkyl.

In some embodiments of the compound of Formula IIB-2, R¹ is—CH(OH)-fused heteroaryl, —C(Me)(OH)-fused heteroaryl; and R² is—C₁-C₆alkyl, —NR⁵ ⁵′, —NHCONR⁵ ⁵′, or —NH—O—R⁵, and R⁵ and R⁵′ areindependently H, C₁-C₆alkyl; R⁵ and R⁵′, together with the atom to whichthey are attached, form a C₂-C₆heterocycloalkyl.

In some embodiments of the compound of Formula IIB-2, R¹ is—CH(OH)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—C(OH)-7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—CH(OH)-7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl, and R² is—NH₂, —CH₃, —NH—O—CH₃, —NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In other embodiments of the compound of Formula IIB-2, R¹ is—C(Me)(OH)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—C(Me)(OH)-7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl, or—C(Me)(OH)-7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl; and R² is—NH₂, —CH₃, —NH—O—CH₃, —NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In other embodiments of the compound of Formula IIB-2, R¹ is—CH(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl,—CH(OH)-(7,7-dimethylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl),—CH(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-ol-3-yl),—CH(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-one-3-yl),—CH(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile-3-yl),or —CH(OH)-(2,3-dihydro-1H-inden-5-yl); and R² is —NH₂—, CH₃, —NH—O—CH₃,—NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In other embodiments of the compound of Formula IIB-2, R¹ is—C(Me)(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl,—C(Me)(OH)-(7,7-dimethylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl),—C(Me)(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-ol-3-yl),—C(Me)(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-one-3-yl),—C(Me)(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile-3-yl),or —C(Me)(OH)-(2,3-dihydro-1H-inden-5-yl); and R² is —NH₂—, CH₃,—NH—O—CH₃, —NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In yet other embodiments of the compound of Formula IIB-2, R¹ is—CH(OH)-(2,3-dihydrobenzofuran-6-yl, or—C(Me)(OH)-2,3-dihydrobenzofuran-6-yl; and R² is —NH₂—, CH₃, —NH—O—CH₃,—NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In yet other embodiments of the compound of Formula IIB-2, R¹ is—CH(OH)-(5,6-dihydro-4H-cyclopenta-[d]thiazol-2-yl) or—C(Me)(OH)-5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl); and R² is —NH₂—,CH₃, —NH—O—CH₃, —NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In some aspects, the present disclosure is directed to compounds ofFormula IIC-1

wherein R¹ is —CH(OH)-fused aryl, —C(Me)(OH)-fused aryl, —CH(OH)-fusedheteroaryl, or C(Me)(OH)-fused heteroaryl; and R² is —C₁-C₆alkyl, —NR⁵⁵′, —NHCONR⁵ ⁵′, or —NH—O—R⁵; and R⁵ and R⁵′ are independently H,C₁-C₆alkyl, R⁵ and R⁵′, together with the atom to which they areattached, form a C₂-C₆heterocycloalkyl.

In some embodiments of the compound of Formula IIC-1, R¹ is—CH(OH)-fused aryl, —C(Me)(OH)-fused aryl; and R² is —C₁-C₆alkyl, —NR⁵⁵′, —NHCONR⁵ ⁵′, or —NH—O—R⁵; and R⁵ and R⁵′ are independently H,C₁-C₆alkyl; or R⁵ and R⁵′, together with the atom to which they areattached, form a C₂-C₆heterocycloalkyl.

In some embodiments of the compound of Formula IIC-1, R¹ is—CH(OH)-fused heteroaryl, —C(Me)(OH)-fused heteroaryl; and R² is—C₁-C₆alkyl, —NR⁵ ⁵′, —NHCONR⁵ ⁵′, or —NH—O—R⁵, and R⁵ and R⁵′ areindependently H, C₁-C₆alkyl; R⁵ and R⁵′, together with the atom to whichthey are attached, form a C₂-C₆heterocycloalkyl.

In some embodiments of the compound of Formula IIC-1, R¹ is—CH(OH)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—C(OH)-7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—CH(OH)-7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl; and R² is—NH₂, —CH₃, —NH—O—CH₃, —NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In other embodiments of the compound of Formula IIC-1, R¹ is—C(Me)(OH)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—C(Me)(OH)-7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl, or—C(Me)(OH)-7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl; and R² is—NH₂, —CH₃, —NH—O—CH₃, —NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In other embodiments of the compound of Formula IIC-1, R¹ is—CH(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl,—CH(OH)-(7,7-dimethylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl),—CH(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-ol-3-yl),—CH(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-one-3-yl),—CH(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile-3-yl),or —CH(OH)-(2,3-dihydro-1H-inden-5-yl); and R² is —NH₂, —CH₃, —NH—O—CH₃,—NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In other embodiments of the compound of Formula IIC-1, R¹ is—C(Me)(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl,—C(Me)(OH)-(7,7-dimethylbicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—C(Me)(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-ol-3-yl),—C(Me)(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-one-3-yl),—C(Me)(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile-3-yl),or —C(Me)(OH)-(2,3-dihydro-1H-inden-5-yl); and R² is —NH₂—, CH₃,—NH—O—CH₃, —NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In yet other embodiments of the compound of Formula IIC-1, R¹ is—CH(OH)-(2,3-dihydrobenzofuran-6-yl, or—C(Me)(OH)-2,3-dihydrobenzofuran-6-yl; and R² is —NH₂—, CH₃, —NH—O—CH₃,—NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In yet other embodiments of the compound of Formula IIC-1, R¹ is—CH(OH)-(5,6-dihydro-4H-cyclopenta-[d]thiazol-2-yl) or—C(Me)(OH)-5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl); and R² is —NH₂,—CH₃, —NH—O—CH₃, —NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In some aspects, the present disclosure is directed to compounds ofFormula IIC-2

wherein R¹ is —CH(OH)-fused aryl, —C(Me)(OH)-fused aryl, —CH(OH)-fusedheteroaryl, or C(Me)(OH)-fused heteroaryl; and R² is —C₁-C₆alkyl, —NR⁵⁵′, —NHCONR⁵ ⁵′, or —NH—O—R⁵; and R⁵ and R⁵′ are independently H,C₁-C₆alkyl, R⁵ and R⁵′, together with the atom to which they areattached, form a C₂-C₆heterocycloalkyl.

In some embodiments of the compound of Formula IIC-2, R¹ is—CH(OH)-fused aryl, —C(Me)(OH)-fused aryl; and R² is —C₁-C₆alkyl, —NR⁵⁵′, —NHCONR⁵ ⁵′, or —NH—O—R⁵; and R⁵ and R⁵′ are independently H,C₁-C₆alkyl; R⁵ and R⁵′, together with the atom to which they areattached, form a C₂-C₆heterocycloalkyl.

In some embodiments of the compound of Formula IIC-2, R¹ is—CH(OH)-fused heteroaryl, —C(Me)(OH)-fused heteroaryl; and R² is—C₁-C₆alkyl, —NR⁵ ⁵′, —NHCONR⁵ ⁵′, or —NH—O—R⁵, and R⁵ and R⁵′ areindependently H, C₁-C₆alkyl; R⁵ and R⁵′, together with the atom to whichthey are attached, form a C₂-C₆heterocycloalkyl.

In some embodiments of the compound of Formula IIC-2, R¹ is—CH(OH)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—C(OH)-7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—CH(OH)-7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl; and R² is—NH₂, —CH₃, —NH—O—CH₃, —NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In other embodiments of the compound of Formula IIC-2, R¹ is—C(Me)(OH)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—C(Me)(OH)-7-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl, or—C(Me)(OH)-7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl; and R² is—NH₂, —CH₃, —NH—O—CH₃, —NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In other embodiments of the compound of Formula IIC-2, R¹ is—CH(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl,—CH(OH)-(7,7-dimethylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl),—CH(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-ol-3-yl),—CH(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-one-3-yl),—CH(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile-3-yl),or —CH(OH)-(2,3-dihydro-1H-inden-5-yl); and R² is —NH₂—, CH₃, —NH—O—CH₃,—NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In other embodiments of the compound of Formula IIC-2, R¹ is—C(Me)(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,—C(Me)(OH)-(7,7-dimethylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl),—C(Me)(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-ol-3-yl),—C(Me)(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-one-3-yl),—C(Me)(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile-3-yl),or —C(Me)(OH)-(2,3-dihydro-1H-inden-5-yl); and R² is —NH₂—, —CH₃,—NH—O—CH₃, —NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In yet other embodiments of the compound of Formula IIC-2, R¹ is—CH(OH)-(2,3-dihydrobenzofuran-6-yl, or—C(Me)(OH)-2,3-dihydrobenzofuran-6-yl; and R² is —NH₂—, CH₃, —NH—O—CH₃,—NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

In yet other embodiments of the compound of Formula IIC-2, R¹ is—CH(OH)-(5,6-dihydro-4H-cyclopenta-[d]thiazol-2-yl) or—C(Me)(OH)-5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl); and R² is —NH₂—,—CH₃, —NH—O—CH₃, —NH—O—CH₂CH₃, —NHCON(CH₃)₂, or

References to Formula I herein also refer to Formulas IA, IA-1, IA-2,IB, IB-1, IB-2, IC-1, and IC-2. References to Formula II herein alsorefer to Formulas IIA, IIA-1, IIA-2, IIB, IIB-1, IIB-2, IIC-1, andIIC-2.

Stereoisomers of compounds of Formula I and Formula II are alsocontemplated by the present disclosure. Thus, the disclosure encompassesall stereoisomers and constitutional isomers of any compound disclosedor claimed herein, including all enantiomers and diastereomers.

Pharmaceutically acceptable salts and solvates of the compounds ofFormula I and Formula II are also within the scope of the disclosure.

Isotopic variants of the compounds of Formula I and Formula II are alsocontemplated by the present disclosure.

Pharmaceutical Compositions and Methods of Administration

The subject pharmaceutical compositions are typically formulated toprovide a therapeutically effective amount of a compound of the presentdisclosure as the active ingredient, or a pharmaceutically acceptablesalt, ester, prodrug, solvate, hydrate or derivative thereof. Wheredesired, the pharmaceutical compositions contain pharmaceuticallyacceptable salt and/or coordination complex thereof, and one or morepharmaceutically acceptable excipients, carriers, including inert soliddiluents and fillers, diluents, including sterile aqueous solution andvarious organic solvents, permeation enhancers, solubilizes andadjuvants.

The subject pharmaceutical compositions can be administered alone or incombination with one or more other agents, which are also typicallyadministered in the form of pharmaceutical compositions. Where desiredthe one or more compounds of the invention and other agent(s) may bemixed into a preparation or both components may be formulated intoseparate preparations to use them in combination separately or at thesame time.

In some embodiments, the concentration of one or more compounds providedin the pharmaceutical compositions of the present invention is less than100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%,14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%,0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%,0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%,0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%,0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or a number inthe range defined by and including any two numbers above) w/w, w/v orv/v.

In some embodiments, the concentration of one or more compounds of theinvention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%,19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%,17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25%15%, 14.75% 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25%, 3%, 12.75%,12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25%,10% 9.75%, 9.50%, 0.25%, 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%,7.25%, 7%, 6.75%, 6.50% 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%,4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%,1.75%, 1.50%, 1.25%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%,0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%,0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%,0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0001%, 0.0003%, 0.0002%,or 0.0001% (or a number in the range defined by and including any twonumbers above) w/w, w/v, or v/v.

In some embodiments, the concentration of one or more compounds of theinvention is in the range from approximately 0.0001% to approximately50%, approximately 0.001% to approximately 40%, approximately 0.01% toapproximately 30%, approximately 0.02% to approximately 29%,approximately 0.03% to approximately 28%, approximately 0.04% toapproximately 27%, approximately 0.05% to approximately 26%approximately 0.06% to approximately 25%, approximately 0.07% toapproximately 24% approximately 0.08% to approximately 23%,approximately 0.09% o approximately 22% approximately 0.1% toapproximately 21%, approximately 0.2% to approximately 20%,approximately 0.3% to approximately 19%, approximately 0.4% toapproximately 18%, approximately 0.5% to approximately 17%,approximately 0.6% to approximately 16%, approximately 0.7% toapproximately 15%, approximately 0.8% to approximately 14%,approximately 0.9% to approximately 12%, approximately 1% toapproximately 10% w/w, w/v or v/v.

In some embodiments, the concentration of one or more compounds of theinvention is in the range from approximately 0.001% to approximately10%, approximately 0.01% to approximately 5%, approximately 0.02% toapproximately 4.5%, approximately 0.03% to approximately 4%,approximately 0.04% to approximately 3.5%, approximately 0.05% toapproximately 3%, approximately 0.06% to approximately 2.5%,approximately 0.07% to approximately 2%, approximately 0.08% toapproximately 1.5%, approximately 0.09% to approximately 1%,approximately 0.1% to approximately 0.9% w/w, w/v or v/v.

In some embodiments, the amount of one or more compounds of theinvention is equal to or less than 10 g, 9.5 g, 90 g, 8.5 g, 8.0 g, 7.5g, 7.0 g, 6.5 g 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4 0 g, 3.5 g, 3.0 g, 2.5 g,2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g,0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g,0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g,0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g,0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g (or a number in therange defined by and including any two numbers above).

In some embodiments, the amount of one or more compounds of theinvention is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g,0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g,0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g,0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g,0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1g, 1.5 g, 2 g, 2.5, 3 g, 3.5 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7.5g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g (or a number in the range defined byand including any two numbers above).

In some embodiments, the amount of one or more compounds of theinvention is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

The compounds according to the invention are effective over a widedosage range for example, in the treatment of adult humans, dosages from0.01 to 1000 mg from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5to 40 mg per day are examples of dosages that may be used. An exemplarydosage is 10 to 30 mg per day. The exact dosage will depend upon theroute of administration, the form in which the compound is administered,the subject to be treated, the body weight of the subject to be treated,and the preference and experience of the attending physician.

A pharmaceutical composition of the invention typically contains anactive ingredient (i.e., a compound of the disclosure) of the presentinvention or a pharmaceutically acceptable salt and/or coordinationcomplex thereof, and one or more pharmaceutically acceptable excipients,carriers, including but not limited to inert solid diluents and fillers,diluents, sterile aqueous solution and various organic solvents,permeation enhancers, solubilizers and adjuvants.

Described below are non-limiting exemplary pharmaceutical compositionsand methods for preparing the same.

Pharmaceutical Compositions for Oral Administration

In some embodiments, the invention provides a pharmaceutical compositionfor oral administration containing a compound of the invention, and apharmaceutical excipient suitable for oral administration.

In some embodiments, the invention provides a solid pharmaceuticalcomposition for oral administration containing: (i) an effective amountof a compound of the invention; optionally (ii) an effective amount of asecond agent, and (iii) a pharmaceutical excipient suitable for oraladministration. In some embodiments, the composition further contains,(iv) an effective amount of a third agent.

In some embodiments, the pharmaceutical composition may be a liquidpharmaceutical composition suitable for oral consumption. Pharmaceuticalcompositions of the invention suitable for oral administration can bepresented as discrete dosage forms, such as capsules, cachets, ortablets, or liquids or aerosol sprays each containing a predeterminedamount of an active ingredient as a powder or in granules, a solution,or a suspension in an aqueous or non-aqueous liquid, an oil-in-wateremulsion, or a water-in-oil liquid emulsion. Such dosage forms can beprepared by any of the methods of pharmacy, but all methods include thestep of bringing the active ingredient into association with thecarrier, which constitutes one or more necessary ingredients. Ingeneral, the compositions are prepared by uniformly and intimatelyadmixing the active ingredient with liquid carriers or finely dividedsolid carriers or both, and then, if necessary, shaping the product intothe desired presentation. For example, a tablet can be prepared bycompression or molding, optionally with one or more accessoryingredients. Compressed tablets can be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such aspowder or granules, optionally mixed with an excipient such as, but notlimited to, a binder, a lubricant, an inert diluent, and/or a surfaceactive or dispersing agent. Molded tablets can be made by molding in asuitable machine a mixture of the powdered compound moistened with aninert liquid diluent.

This invention further encompasses anhydrous pharmaceutical compositionsand dosage forms composing an active ingredient, since water canfacilitate the degradation of some compounds. For example, water may beadded (e.g., 5%) in the pharmaceutical arts as a means of simulatinglong-term storage in order to determine characteristics such asshelf-life or the stability of formulations over time. Anhydrouspharmaceutical compositions and dosage forms of the invention can beprepared using anhydrous or low moisture containing ingredients and lowmoisture or low humidity conditions. Pharmaceutical compositions anddosage forms of the invention which contain lactose can be madeanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected. An anhydrouspharmaceutical composition may be prepared and stored such that itsanhydrous nature is maintained. Accordingly, anhydrous compositions maybe packaged using materials known to prevent exposure to water such thatthey can be included in suitable formulary kits. Examples of suitablepackaging include, but are not limited to, hermetically sealed foils,plastic or the like, unit dose containers, blister packs, and strippacks.

An active ingredient can be combined in an intimate admixture with apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques. The carrier can take a wide variety of formsdepending on the form of preparation desired for administration. Inpreparing the compositions for an oral dosage form, any of the usualpharmaceutical media can be employed as carriers, such as, for example,water, glycols, oils, alcohols, flavoring agents, preservatives,coloring agents, and the like in the case of oral liquid preparations(such as suspensions, solutions, and elixirs) or aerosols, or carrierssuch as starches, sugars, micro-crystalline cellulose, diluents,granulating agents, lubricants, binders, and disintegrating agents canbe used in the case of oral solid preparations, in some embodimentswithout employing the use of lactose. For example, suitable carriersinclude powders, capsules, and tablets with the solid oral preparations.If desired, tablets can be coated by standard aqueous or nonaqueoustechniques.

Binders suitable for use in pharmaceutical compositions and dosage formsinclude, but are not limited to, corn starch, potato starch, or otherstarches, gelatin, natural and synthetic gums such as acacia, sodiumalginate, alginic acid, other alginates, powdered tragacanth, guar gum,cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate,carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch,hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixturesthereof.

Examples of suitable fillers for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pro-gelatinized starch and mixtures thereof.

Disintegrants may be used in the compositions of the invention toprovide tablets that disintegrate when exposed to an aqueousenvironment. Too much of a disintegrant may produce tablets which maydisintegrate in the bottle. Too little may be insufficient fordisintegration to occur and may thus alter the rate and extent ofrelease of the active ingredient(s) from the dosage form. Thus, asufficient amount of disintegrant that is neither too little nor toomuch to detrimentally alter the release of the active ingredient(s) maybe used to form the dosage forms of the compounds disclosed herein. Theamount of disintegrant used may vary based upon the type of formulationand mode of administration, and may be readily discernible to those ofordinary skill in the art. About 0.5 to about 15 weight percent ofdisintegrant, or about 1 to about 5 weight percent of disintegrant, maybe used in the pharmaceutical composition. Disintegrants that can beused to form pharmaceutical compositions and dosage forms of theinvention include, but are not limited to, agar-agar alginic acid,calcium carbonate, microcrystalline cellulose, croscarmellose sodium,crospovidone, polacrilin pottassium, sodium starch glycolate, potato ortapioca starch, other starches, pre-gelatinized starch, other starches,clays, other algins, other celluloses, gums or mixtures thereof.

Lubricants which can be used to form pharmaceutical compositions anddosage forms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, ormixtures thereof. Additional lubricants include, for example, a syloidsilica gel, a coagulated aerosol of synthetic silica, or mixturesthereof. A lubricant can optionally be added, in an amount of less thanabout 1 weight percent of the pharmaceutical composition.

When aqueous suspensions and/or elixirs are desired for oraladministration, the active ingredient therein may be combined withvarious sweetening or flavoring agents, coloring matter or dyes and, ifso desired, emulsifying and/or suspending agents, together with suchdiluents as water, ethanol, propylene glycol, glycerin and variouscombinations thereof.

The tablets can be uncoated or coated by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate canbe employed. Formulations for oral use can also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate ofkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example, peanut oil, liquidparaffin or olive oil.

Surfactant which can be used to form pharmaceutical compositions anddosage forms of the invention include, but are not limited to,hydrophilic surfactants, lipophilic surfactants, and mixtures thereof.That is, a mixture of hydrophilic surfactants may be employed, a mixtureof lipophilic surfactants may be employed, or a mixture of at least onehydrophilic surfactant and at least one lipophilic surfactant may beemployed.

A suitable hydrophilic surfactant may generally have an HLB value of atleast 10, while suitable lipophilic surfactants may generally have anHLB value of or less than about 10. An empirical parameter used tocharacterize tint relative hydrophilicity and hydrophobicity ofnon-ionic amphiphilic compounds is the hydrophilic-lipophilic balance(“HLB” value) Surfactants with lower HLB values are more lipophilic orhydrophobic, and have greater solubility in oils, while surfactants withhigher HLB values are more hydrophilic, and have greater solubility inaqueous solutions.

Hydrophilic surfactants are generally considered to be those compoundshaving an HLB value greater than about 10, as well as anionic, cationic,or zwitterionic compounds for which the HLB scale is not generallyapplicable. Similarly, lipophilic (i.e., hydrophobic) surfactants arecompounds having an HLB value equal to or less than about 10. However,HLB value of a surfactant is merely a rough guide generally used toenable formulation of industrial, pharmaceutical and cosmetic emulsions.

Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionicsurfactants include, but are not limited to, alkylammnium salts, fusidicacid salts, fatty acid derivatives of amino acids, oligopeptides, andpolypeptides, glyceride derivatives of amino acids, oligopeptides, andpolypeptides, lecithins and hydrogenated lecithins; lysolecithins andhydrogenated lysolecithins, phospholipids and derivatives thereof,lysophospholipids and derivatives thereof, carnitine fatty acid estersalts; salts of alkyl sulfates; fatty acid salts, sodium docusate, acyllactylates; mono- and di-acetylated tartaric acid esters of mono- anddi-glycerides; succinylated mono- and di-glycerides citric acid estersof mono- and di-glycerides; and mixtures thereof.

Within the aforementioned group, ionic surfactants include by way ofexample lecithins, lysolecithin, phospholipids, lysophospholipids andderivatives thereof; carnitine fatty acid ester salts, salts ofalkylsulfates; fatty acid salts, sodium docusate; acylactylates; mono-and di-acetylated tartaric acid esters of mono- and di-glycerides;succinylated mono- and di-glycerides; citric acid esters of mono- anddi-glycerides; and mixtures thereof.

Ionic surfactants may be the ionized forms of lecithin, lysolecithin,phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol,phosphatidic acid, phosphatidylserine, lysophosphatidylcholine,lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidicacid, lysophosphatidylserine, PEG-phosphatidylethanolamine,PVP-phosphatidylethanolamine, lactylic esters of fatty acids,stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides,mono/diacetylated tartaric acid esters of mono/diglycerides, citric acidesters of mono/diglycerides, cholylsarcosine, caproate, caprylate,caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate,linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate,lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, andsalts and mixtures thereof.

Hydrophilic non-ionic surfactants may include, but are not limited to,alkylglucosides, alkylmaltosides; alkylthioglucosides; laurylmacrogolglycerides, polyoxyalkylene alkyl ethers such as polyethyleneglycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethyleneglycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esterssuch as polyethylene glycol fatty acids monoesters and polyethyleneglycol fatty acids diesters; polyethylene glycol glycerol fatty acidesters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fattyacid esters such as polyethylene glycol sorbitan fatty acid esters;hydrophilic transesterification products of a polyol with at least onemember of the group consisting of glycerides, vegetable oils,hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylenesterols, derivatives, and analogues thereof; polyoxyethylated vitaminsand derivatives thereof; polyoxyethylene-polyoxypropylene blockcopolymers; and mixtures thereof; polyethylene glycol sorbitan fattyacid esters and hydrophilic transesterification products of a polyolwith at least one member of the group consisting of triglycerides,vegetable oils, and hydrogenated vegetable oils. The polyol may beglycerol, ethylene glycol, polyethylene glycol, sorbitol, propyleneglycol, pentaerythritol, or a saccharide.

Other hydrophilic-non-ionic surfactants include, without limitation,PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate,PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32distearate, PEG-40 stearate, PEG- 100 stearate, PEG-20 dilaurate, PEG-25glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate,PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryllaurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenatedcastor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides,polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitanlaurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearylether, tocopheryl PEG-100 succinate, PEG-24 cholesterol,polyglyceryl-1Ooleate, Tween 40, Tween 60, sucrose monostearate, sucrosemono laurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG15-100 octyl phenol series, and poloxamers.

Suitable lipophilic surfactants include, by way of example only fattyalcohols; glycerol fatty acid esters; acetylated glycerol fatty acidesters; lower alcohol fatty acids esters; propylene glycol fatty acidesters, sorbitan fatty acid esters, polyethylene glycol sorbitan fattyacid esters; sterols and sterol derivatives; polyoxyethylated sterolsand sterol derivatives, polyethylene glycol alkyl ethers; sugar esters;sugar ethers; lactic acid derivatives of mono- and di-glycerides,hydrophobic transesterification products of a polyol with at least onemember of the group consisting of glycerides, vegetable oils,hydrogenated vegetable oils, fatty acids and sterols; oil-solublevitamins/vitamin derivatives; and mixtures thereof. Within this group,preferred lipophilic surfactants include glycerol fatty acid esters,propylene glycol fatty acid esters, and mixtures thereof, or arehydrophobic transesterification products of a polyol with at least onemember of the group consisting of vegetable oils, hydrogenated vegetableoils, and triglycerides.

In one embodiment, the composition may include a solubilizer to ensuregood solubilization and/or dissolution of the compound of the presentinvention and to minimize precipitation of the compound of the presentinvention. This can be especially important for compositions fornon-oral use, e.g., compositions for injection. A solubilizer may alsobe added to increase the solubility of the hydrophilic drug and/or othercomponents, such as surfactants, or to maintain the composition as astable or homogeneous solution or dispersion.

Examples of suitable solubilizers include, but are not limited to, thefollowing: alcohols and polyols, such as ethanol, isopropanol, butanol,benzyl alcohol, ethylene glycol, propylene glycol, butanediols andisomers thereof, glycerol, pentaerythritol, sorbitol, mannitol,transcutol, dimethyl isosorbide, polyethylene glycol, polypropyleneglycol, polyvinylalcohol, hydroxypropyl methylcellulose and othercellulose derivatives, cyclodextrins and cyclodextrin derivatives;ethers of polyethylene glycols having an average molecular weight ofabout 200 to about 6000. such as tetrahydrofurfuryl alcohol PEG ether(glycofurol) or methoxy PEG; amides and other nitrogen-containingcompounds such as 2-pyrrolidone, 2-piperidone, ε-caprolactam,N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone,N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone, esterssuch as ethyl propionate, tributylcitrate, acetyl triethylcitrate,acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate,ethyl butyrate, triacetin, propylene glycol monoacetate, propyleneglycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactoneand isomers thereof, β-butyrolactone and isomers thereof; and othersolubilizers known in the art, such as dimethyl acetamide, dimethylisosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycolmonoethyl ether, and water.

Mixtures of solubilizes may also be used. Examples include, but notlimited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate,dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone,polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol,transcutol, propylene glycol, and dimethyl isosorbide. Particularlypreferred solubilizers include sorbitol, glycerol, triacetin, ethylalcohol, PEG-400, glycofurol and propylene glycol.

The amount of solubilizer that can be included is not particularlylimited. The amount of a given solubilizer may be limited to abioacceptable amount, which may be readily determined by one of skill inthe art. In some circumstances, it may lie be advantageous to includeamounts of solubilizers far in excess of bioacceptable amounts, forexample to maximize the concentration of the drug, with excesssolubilizer removed prior to providing the composition to a subjectusing conventional techniques, such as distillation or evaporation.Thus, if prevent, the solubilizer can be in a weight ratio of 10%, 25%o,50%), 100%o, or up to about 200%> by weight, based on the combinedweight of the drug, and other excipients. If desired, very small amountsof solubilizer may also be used, such as 5%>, 2%>, 1%) or even less.Typically, the solubilizer may be present in an amount of about 1%< toabout 100%, more typically about 5%< to about 25%< by weight.

The composition can further include one or more pharmaceuticallyacceptable additives and excipients. Such additives and excipientsinclude, without limitation, detackifiers, anti-foaming agents,buffering agents, polymers, antioxidants, preservatives, chelatingagents, viscomodulators, tonicifiers, flavorants, colorants, odorants,opacifiers, suspending agents, binders, fillers, plasticizers,lubricants, and mixtures thereof.

In addition, an acid or a base may be incorporated into the compositionto facilitate processing, to enhance stability, or for other reasons.Examples of pharmaceutically acceptable bases include amino acids, aminoacid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide,sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate,magnesium hydroxide, magnesium aluminum silicate, synthetic aluminumsilicate, synthetic hydrocalcite, magnesium aluminum hydroxide,diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine,triethylamine, triisopropanolamine, trimethylamine,tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable arebases that are salts of a pharmaceutically acceptable acid, such asacetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonicacid, amino acids, ascorbic acid, benzoic acid, boric acid, butyricacid, carbonic acid, citric acid, fatty acids, formic acid, fumaricacid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lacticacid, maleic acid oxalic acid, para-bromophenylsulfonic acid, propionicacid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinicacid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonicacid, uric acid, and the like. Salts of polyprotic acids, such as sodiumphosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphatecan also be used. When the base is a salt, the cation can be anyconvenient and pharmaceutically acceptable cation, such as ammonium,alkali metals, alkaline earth metals, and the like. Example may includebut not limited to, sodium, potassium, lithium, magnesium, calcium andammonium.

Suitable acids are pharmaceutically acceptable organic or inorganicacids. Examples of suitable inorganic acids include hydrochloric acid,hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boricacid, phosphoric acid, and the like. Examples of suitable organic acidsinclude acetic acid, acrylic acid, adipic acid, alginic acid,alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boricacid, butyric acid, carbonic acid, citric acid, fatty acids, formicacid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbicacid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid,para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid,salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid,thioglycolic acid, toluenesulfonic acid, uric acid and the like.

Pharmaceutical Compositions for Injection

In some embodiments, the invention provides a pharmaceutical compositionfor injection containing a compound of the present invention and apharmaceutical excipient suitable for injection. Components and amountsof agents in the compositions are as described herein.

The forms in which the novel compositions of the present invention maybe incorporated for administration by injection include aqueous or oilsuspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, orpeanut oil, as well as elixirs, mannitol. dextrose, or a sterile aqueoussolution, and similar pharmaceutical vehicles.

Aqueous solutions in saline are also conventionally used for injection.Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and thelike (and suitable mixtures thereof), cyclodextrin derivatives, andvegetable oils may also be employed. The proper fluidity can bemaintained, for example, by the use of a coating, such as lecithin, forthe maintenance of the required particle size in the case of dispersionand by the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating the compoundof the present invention in the required amount in the appropriatesolvent with various other ingredients as enumerated above, as required,followed by filtered sterilization. Generally, dispersions are preparedby incorporating the various sterilized active ingredients into asterile vehicle which contains the basic dispersion medium and therequired other ingredients from those enumerated above. In the case ofsterile powders for the preparation of sterile injectable solutions,certain desirable methods of preparation are vacuum-drying andfreeze-drying techniques which yield a powder of the active ingredientplus any additional desired ingredient from a previouslysterile-filtered solution thereof.

Pharmaceutical Compositions for Topical (e.g. Transdermal) Delivery

In some embodiments, the invention provides a pharmaceutical compositionfor transdermal delivery containing a compound of the present inventionand a pharmaceutical excipient suitable for transdermal delivery.

Compositions of the present invention can be formulated intopreparations in solid, semisolid, or liquid forms suitable for local ortopical administration, such as gels, water soluble jellies, creams,lotions, suspensions, foams, powders, slurries, ointments, solutions,oils, pastes, suppositories, sprays, emulsions, saline solutions,dimethylsulfoxide (DMSO)-based solutions. In general, carriers withhigher densities are capable of providing an area with a prolongedexposure to the active ingredients. In contrast, a solution formulationmay provide more immediate exposure of the active ingredient to thechosen area.

The pharmaceutical compositions also may comprise suitable solid or gelphase carriers or excipients, which are compounds that allow increasedpenetration of, or assist in the delivery of, therapeutic moleculesacross the stratum corneum permeability barrier of the skin. There aremany of these penetration-enhancing molecules known to those trained inthe art of topical formulation.

Examples of such carriers and excipients include, but are not limitedto, humectants (e.g., urea), glycols, (e.g., propylene glycol), alcohols(e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g.,isopropyl myristate and sodium lauryl sulfate), pyrrolidones, glycerolmonolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides,alkanes, alkanols, water, calcium carbonate, calcium phosphate, varioussugars, starches, cellulose derivatives, gelatin, and polymers such aspolyethylene glycols.

Another exemplary formulation for use in the methods of the presentinvention employs transdermal delivery devices (“patches”). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of a compound of the present invention in controlled amounts,either with or without another agent.

The construction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art. See. e.g., U.S. Pat.Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructedfor continuous, pulsatile, or on demand delivery of pharmaceuticalagents.

Pharmaceutical Compositions for Inhalation

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be inhaled directly from thenebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder compositions may be administered,preferably orally or nasally, from devices that deliver the formulationin an appropriate manner.

Other Pharmaceutical Compositions

Pharmaceutical compositions may also be prepared from compositionsdescribed herein and one or more pharmaceutically acceptable excipientssuitable for sublingual, buccal, rectal, intraosseous, intraocular,intranasal, epidural, intraspinal administration. Preparations for suchpharmaceutical compositions are well-known in the art. See, e.g.,Anderson, Philip O.; Knoben, James E., Troutman, William G, eds.,Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Prattand Taylor, eds. Principles of Drug Action, Third Edition, ChurchillLivingston, N.Y., 1990, Katzung, ed., Basic and Clinical PharmacologyNinth Edition, McGraw Hill, 2003ybg; Goodman and Gilman, eds. ThePharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001,Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams &Wilkins, 2000, Martindale. The Extra Pharmacopoeia, Thirty-SecondEdition (The Pharmaceutical Press, London, 1999), all of which areincorporated by reference herein in their entirety.

Administration of the compounds or pharmaceutical composition of thepresent invention can be effected by any method that enables delivery ofthe compounds to the site of action. These methods include oral routes,intraduodenal routes, parenteral injection (including intravenous,intraarterial, subcutaneous, intramuscular, intravascular,intraperitoneal or infusion), topical (e.g. transdermal application),rectal administration, via local delivery by catheter or stent orthrough inhalation. Compounds can also be administered intraadiposallyor intrathecally.

The amount of the compound administered will be dependent on the subjectbeing treated, the severity of the disorder or condition, the rate ofadministration, the disposition of the compound and the discretion ofthe prescribing physician. However, an effective dosage is in the rangeof about 0.001 to about 100 mg per kg body weight per day, preferablyabout 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kghuman, this would amount to about 0.05 to 7 g/day, preferably about 0.05to about 2.5 g/day. In some instances, dosage levels below the lowerlimit of the aforesaid range may be more than adequate, while in othercases still larger doses may be employed without causing any harmfulside effect, e.g. by dividing such larger doses into several small dosesfor administration throughout the day.

In some embodiments, a compound of the invention is administered in asingle dose.

Typically, such administration will be by injection e.g., intravenousinjection, in order to introduce the agent quickly. However, otherroutes may be used as appropriate. A single dose of a compound of theinvention may also be used for treatment of an acute condition.

In some embodiments, a compound of the invention is administered inmultiple doses. Dosing may be about once, twice, three times, fourtimes, five times, six times, or more than six times per day. Dosing maybe about once a month, once every two weeks, once a week, or once everyother day. In another embodiment a compound of the invention and anotheragent are administered together about once per day to about 6 times perday. In another embodiment the administration of a compound of theinvention and an agent continues for less than about 7 days. In yetanother embodiment the administration continues for more than about 6,10, 14, 28 days, two months, six months, or one year. In some cases,continuous dosing is achieved and maintained as long as necessary.

Administration of the compounds of the invention may continue as long asnecessary. In some embodiments, a compound of the invention isadministered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In someembodiments, a compound of the invention is administered for less than28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, a compound ofthe invention is administered chronically on an ongoing basis, e.g., forthe treatment of chronic effects.

An effective amount of a compound of the invention may be administeredin either single or multiple doses by any of the accepted modes ofadministration of agents having similar utilities, including rectal,buccal intranasal and transdermal routes, by intra-arterial injection,intravenously, intraperitoneally, patenterally, intramuscularly,subcutaneously, orally, topically, or as an inhalant.

The compositions of the invention may also be delivered via animpregnated or coated device such as a stent, for example, or an arteryinserted cylindrical polymer. Such a method of administration may, forexample, aid in the prevention or amelioration of restenosis followingprocedures such as balloon angioplasty. Without being bound by theory,compounds of the invention may slow or inhibit the migration andproliferation of smooth muscle cells in the arterial wall whichcontribute to restenosis. A compound of the invention may beadministered, for example, by local delivery from the struts of a stent,from a stent graft, from grafts, or from the cover or sheath of a stent.In some embodiments, a compound of the invention is admixed with amatrix. Such a matrix may be a polymeric matrix, and may serve to bondthe compound to the stent. Polymeric matrices suitable for such use,include, for example, lactone-based polyesters or copolyesters such aspolylactide, polycaprolactonglycolide, polyorthoesters, polyanhydrides,polyaminoacids, polysaccharides, polyphosphazenes, poly (ether-ester)copolymers (e.g., PEO-PLLA), polydimethylsiloxane,poly(ethylene-vinylacetate), acrylate-based polymers or copolymers (e.g.polyhydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone),fluorinated polymers such as polytetrafluoroethylene and celluloseesters. Suitable matrices may be nondegrading or may degrade with time,releasing the compound or compounds. Compounds of the invention may beapplied to the surface of the stent by various methods such its dip/spincoating, spray coating, dip-coating, and/or brush-coating. The compoundsmay be applied in a solvent and the solvent may be allowed to evaporate,thus forming a layer of compound onto the stent. Alternatively, thecompound may be located in the body of the stent or graft, for examplein microchannels or micropores. When implanted, the compound diffusesout of the body of the stent to contact the arterial wall. Such stentsmay be prepared by dipping a stent manufactured to contain suchmicropores or microchannels into a solution of the compound of theinvention in a writable solvent, followed by evaporation of the solvent.Excess drug on the surface of the stent may be removed via an additionalbrief solvent wash. In yet other embodiments, compounds of the inventionmay be covalently linked to a stent or graft. A covalent linker may beused which degrades in vivo, leading to the release of the compound ofthe invention. Any bio-labile linkage may be used for such a purpose,such as ester, amide or anhydride linkages. Compounds of the inventionmay additionally be administered intravascularly from a balloon usedduring angioplasty. Extravascular administration of the compounds viathe pericard or via advential application of formulations of theinvention may also be performed to decrease restenosis.

A variety of stent devices which may be used as described are disclosed,for example, in the following references, all of which are herebyincorporated by reference U.S. Pat. Nos. 5,451,233; 5,040,548;5,061,273; 5,496,346; 5,292,531; 5,674,278; 3,657,744; 4,739,762;5,195,984; 5,292,331; 5,674,278; 5,879,382; 6,344,053.

The compounds of the invention may be administered in dosages. It isknown in the art that due to inter subject variability in compoundpharmacokinetics, individualization of dosing regimen is necessary foroptimal therapy. Dosing for a compound of the invention may be found byroutine experimentation in light of the instant disclosure.

When a compound of the invention is administered in a composition thatcomprises one or more agents, and the agent has a shorter half-life thanthe compound of the invention unit dose forms of the agent and thecompound of the invention may be adjusted accordingly

The subject pharmaceutical composition may, for example, be in a formsuitable for oral administration as a tablet, capsule, pill, powder,sustained release formulations, solution, suspension, for parenteralinjection as a sterile solution, suspension or emulsion, for topicaladministration as an ointment or cream or for rectal administration as asuppository. The pharmaceutical composition may be in unit dosage formssuitable for single administration of precise dosages. Thepharmaceutical composition will include a conventional pharmaceuticalcarrier or excipient and a compound according to the invention as anactive ingredient. In addition, it may include other medicinal orpharmaceutical agents, carriers, adjuvants, etc.

Exemplary parenteral administration forms include solutions orsuspensions of active compound in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms can be suitably buffered, if desired.

Methods of Use

The method typically comprises administering to a subject atherapeutically effective amount of a compound of the invention. Thetherapeutically effective amount of the subject combination of compoundsmay vary depending upon the intended application (in vitro or in vivo),or the subject and disease condition being treated, e.g., the weight andage of the subject, the severity of the disease condition, the manner ofadministration and the like, which can readily be determined by one ofordinary skill in the art. The term also applies to a dose that willinduce a particular response in target cells, e.g., reduction ofproliferation or downregulation of activity of a target protein. Thespecific dose will vary depending on the particular compounds chosen,the dosing regimen to be followed, whether it is administered incombination with other compounds, timing of administration, the tissueto which it is administered, and the physical delivery system in whichit is carried.

As used herein, the term “IC₅₀” refers to the half maximal inhibitoryconcentration of an inhibitor in inhibiting biological or biochemicalfunction. This quantitative measure indicates how much of a particularinhibitor is needed to inhibit a given biological process (or componentof a process, i.e. an enzyme, cell, cell receptor or microorganism) byhalf. In other words, it is the half maximal (50%) inhibitoryconcentration (IC) of a substance (50% IC, or IC50). EC50 refers to theplasma concentration required for obtaining 50%> of a maximum effect invivo.

In some embodiments, the subject methods utilize a PRMT5 inhibitor withan IC50 value of about or less than a predetermined value, asascertained in an in vitro assay. In some embodiments, the PRMT5inhibitor inhibits PRMT5 a with an IC50 value of about 1 nM or less, 2nM or less, 5 nM or less, 7 nM or less, 10 nM or less, 20 nM or less, 30nM or less, 40 nM or less, 50 nM or less, 60 nM or less, 70 nM or less,80 nM or less, 90 nM or less, 100 nM or less, 120 nM or less, 140 nM orless, 150 nM or less, 160 nM or less, 170 nM or less, 180 nM or less,190 nM or less, 200 nM or less, 225 nM or less, 250 nM or less, 275 nMor less, 300 nM or less, 325 nM or less, 350 nM or less, 375 nM or less,400 nM or less, 425 nM or less, 450 nM or less, 475 nM or less, 500 nMor less, 550 nM or less, 600 nM or less, 650 nM or less, 700 nM or less,750 nM or less, 800 nM or less, 850 nM or less, 900 nM or less, 950 nMor less, 1 μM or less, 1.1 μM or less, 1.2 μM or less, 1.3 μM or less,1.4 μM or less, 1.5 μM or less, 1.6 μM or less, 1.7 μM or less, 1.8 μMor less, 1.9 μM or less, 2 μM or less, 5 μM or less, 10 μM or less, 15μM or less, 20 μM or less, 25 μM or less, 30 μM or less, 40 μM or less,50 μM, 60 μM, 70 μM, 80 μM, 90 μM, 100 μM, 200 μM, 300 μM, 400 μM, or500 μM, or less, (or a number in the range defined by and including anytwo numbers above).

In some embodiments, the PRMT5 inhibitor selectively inhibits PRMT5 awith an IC50 value that is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20,25, 30, 35, 40, 45, 50, 100, or 1000 times less (or a number in therange defined by and including any two numbers above) than its IC50value against one, two, or three other PRMTs.

In some embodiments, the PRMT5 inhibitor selectively inhibits PRMT5 awith an IC50 value that is less than about 1 nM, 2 nM, 5 nM, 7 nM, 10nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM,120nM, 140nM, 150 nM, 160 nM, 170 nM, 180 nM, 190 nM, 200 nM, 225 nM,250 nM, 275 nM, 300 nM, 325 nM, 350 nM, 375 nM, 400 nM, 425 nM, 450 nM,475 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM, 800 nM, 850 nM,900 nM, 950 nM, 1 μM, 12 μM, 1.3 μM, 1.4 μM, 1.5 μM, 1.6 μM, 1.7 μM, 1.8μM, 1.9 μM, 2 μM, 5 μM, 10 μM, 15 μM, 20 μM, 25 μM, 30 μM, 40 μM, 50 μM,60 μM, 70 uM, 80 μM, 90 μM, 100 μM, 200 μM, 300 μM, 400 μM, or 500 μM(or in the range defined by and including any two numbers above), andsaid IC50 value is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30,35, 40, 45, 50, 100, or 1000 times less (or a number in the rangedefined by and including any two numbers above) than its IC50 valueagainst one, two or three other PRMTs.

The subject methods are useful for treating a disease conditionassociated with PRMT5. Any disease condition that results directly orindirectly from an abnormal activity or expression level of PRMT5 can bean intended disease condition.

Different disease conditions associated with PRMT5 have been reported.PRMT5 has been implicated, for example, in a variety of human cancers aswell as a number of hemoglobinopathies.

Non-limiting examples of such conditions include but are not limited toAcanthoma, Acinic cell carcinoma, Acoustic neuroma, Acral lentiginousmelanoma, Acrospiroma, Acute eosinophilic leukemia, Acute lymphoblasticleukemia, Acute lymphocytic leukemia, Acute megakaryoblastic leukemia,Acute monocytic leukemia, Acute myeloblasts leukemia with maturation,Acute myeloid dendritic cell leukemia, Acute myeloid leukemia, Acutemyelogenous leukemia, Acute promyelocytic leukemia, Adamantinoma,Adenocarcinoma, Adenoid cystic carcinoma, Adenoma, Adenomatoidodontogenic tumor, Adrenocortical carcinoma. Adult T-cell leukemia,Aggressive NK-cell leukemia, AIDS-Related Cancers, AIDS-relatedlymphoma, Alveolar soft part sarcoma, Ameloblastic fibroma, Anal cancer,Anaplastic large cell lymphoma, Anaplastic thyroid cancer,Angioimmunoblastic T-cell lymphoma, Angiomyolipoma, Angiosarcoma,Appendix cancer, Astrocytoma, Atypical teratoid rhabdoid tumor, Basalcell carcinoma, Basal-like carcinoma, B-cell leukemia, B-cell lymphoma,Bellini duct carcinoma, Biliary tract cancer, Bladder cancer, Blastoma,Bone Cancer, Bone tumor, Brain Stem Glioma, Brain Tumor, Breast Cancer,Brenner tumor, Bronchial Tumor, Bronchioloalveolar carcinoma, Browntumor, Burkin's lymphoma, Cancer of Unknown Primary Site, CarcinoidTumor, Carcinoma, Carcinoma in situ, Carcinoma of the penis, Carcinomaof Unknown Primary Site, Carcinosarcoma, Castleman's Disease, CentralNervous System Embryonal Tumor, Cerebellar Astrocytoma, CerebralAstrocytoma, Cervical Cancer, Cholangiocarcinoma, Chondroma,Chondrosarcoma, Chordoma, Choriocarcinoma, Choroid plexus papilloma,Chronic Lymphocytic Leukemia, Chronic monocytic leukemia, Chronicmyelogenous leukemia, Chronic Myeloproliferative Disorder, Chronicneutrophilic leukemia, Clear-cell tumor, Colon Cancer, Colorectalcancer, Craniopharyngioma, Cutaneous T-cell lymphoma, Degos disease,Dermatofibrosarcoma protuberans, Dermoid cyst, Desmoplastic small roundcell rumor, Diffuse large B cell lymphoma, Dysembryoplasticneuroepithelial tumor, Embryonal carcinoma, Endodermal sinus tumor,Endometrial cancer, Endometrial Uterine Cancer, Endometrioid tumor,Enteropathy-associated T-cell lymphoma, Ependymoblastoma, Ependymoma,Epidermoid cancer, Epithelioid sarcoma, Erythroleukemia, Esophagealcancer, Esthesioneuroblastoma, Ewing family of Tumor, Ewing FamilySarcoma, Ewing's sarcoma, Extracranial Germ Cell Tumor, ExtragonadalGerm Cell Tumor, Extrahepatic Bile Duct Cancer, Extramammary Paget'sdisease, Fallopian tube cancer, Fetus in fetu, Fibroma, Fibrosarcoma,Follicular lymphoma, Follicular thyroid cancer, Gallbladder Cancer,Gallbladder cancer, Ganglioglioma, Ganglioneuroma, Gastric Cancer,Gastric lymphoma, Gastrointestinal cancer, Gastrointestinal CarcinoidTumor, Gastrointestinal Stromal Tumor, Gastrointestinal stromal tumor,Germ cell tumor, Germinoma, Gestational choriocarcinoma, GestationalTrophoblastic Tumor, Giant cell tumor of bone, Glioblastoma multiforme,Glioma, Gliomatosis cerebri, Glomus tumor, Glucagonoma, Gonadoblastoma,Granulosa cell tumor, Hairy Cell Leukemia, Head and Neck Cancer, Headand neck cancer, Heart cancer, Hemoglobinopathies such as b-thalassemiaand sickle cell disease (SCD), Hemangioblastoma, Hemangiopericytoma,Hemangiosarcoma, Hematological malignancy, Hepatocellular carcinoma,Hepatosplenic T-cell lymphoma, Hereditary breast-ovarian cancersyndrome, Hodgkin Lymphoma, Hodgkin's lymphoma, Hypopharyngeal Cancer,Hypothalamic Glioma, Inflammatory breast cancer, Intraocular Melanoma,Islet cell carcinoma, Islet Cell Tumor, Juvenile myelomonocyticleukemia, Kaposi Sarcoma, Kaposi's sarcoma, Kidney Cancer, Klatskintumor, Krukenberg tumor, Laryngeal Cancer, Laryngeal cancer, Lentigomaligna melanoma, Leukemia, Lip and Oral Cavity Cancer, Liposarcoma,Lung cancer, Luteoma, Lymphangioma, Lymphangiosarcoma,Lymphoepithelioma, Lymphoid leukemia, Lymphoma, Macroglobulinemia,Malignant Fibrous Histiocytoma, Malignant fibrous histiocytoma,Malignant Fibrous Histiocytoma of Bone, Malignant Glioma, MalignantMesothelioma, Malignant peripheral nerve sheath tumor, Malignantrhabdoid tumor, Malignant triton tumor, MALT lymphoma, Mantle celllymphoma, Mast cell leukemia, Mastocytosis, Mediastinal germ cell tumor,Mediastinal tumor, Medullary thyroid cancer, Medulloblastoma,Medulloblastoma, Medulloepithelioma, Melanoma, Melanoma, Meningioma,Merkel Cell Carcinoma, Mesothelioma, Mesothelioma, Metastatic SquamousNeck Cancer with Occult Primary, Metastatic urothelial carcinoma, MixedMullerian tumor, Monocytic leukemia, Mouth Cancer, Mucinous tumor,Multiple Endocrine Neoplasia Syndrome, Multiple Myeloma, Multiplemyeloma, Mycosis Fungoides, Mycosis fungoides, Myelodysplasia Disease,Myelodysplasia Syndromes, Myeloid leukemia, Myeloid sarcoma,Myeloproliferative Disease, Myxoma, Nasal Cavity Cancer, NasopharyngealCancer, Nasopharyngeal carcinoma, Neoplasm, Neurinoma, Neuroblastoma,Neuroblastoma, Neurofibroma, Neuroma, Nodular melanoma, Non-HodgkinLymphoma, Non-Hodgkin lymphoma, Nonmelanoma Skin Cancer, Non-Small CellLung Cancer, Ocular oncology, Oligoastrocytoma, Oligodendroglioma,Oncocytoma, Optic nerve sheath meningioma, Oral Cancer, Oral cancer,Oropharyngeal Cancer, Osteosarcoma, Osteosarcoma, Ovarian Cancer,Ovarian cancer, Ovarian Epithelial Cancer, Ovarian Germ Cell Tumor,Ovarian Low Malignant Potential Tumor, Paget's disease of the breast,Pancoast tumor, Pancreatic Cancer, Pancreatic cancer, Papillary thyroidcancer, Papillomatosis, Paraganglioma, Paranasal Sinus Cancer,Parathyroid Cancer, Penile Cancer, Perivascular epithelioid cell tumor,Pharyngeal Cancer, Pheochromocytoma, Pineal Parenchymal Tumor ofIntermediate Differentiation, Pineoblasloma, Pituicytoma, Pituitaryadenoma, Pituitary tumor, Plasma Cell Neoplasm Pleuropulmonary blastoma,Polyembryoma, Precursor T-lymphoblastic lymphoma, Primary centralnervous system lymphoma, Primary effusion lymphoma, PrimaryHepatocellular Cancer, Primary Liver Cancer, Primary peritoneal cancer,Primitive neuroectodermal tumor, Prostate cancer, Pseudomyxomaperitonei, Rectal Cancer, Renal cell carcinoma, Respiratory TractCarcinoma Involving the NUT Gene onChromosome 15, Retinoblastoma,Rhabdomyoma, Rhabdomyosarcoma, Richter's transformation, Sacrococcygealteratoma, Salivary Gland Cancer, Sarcoma, Schwannomatosis, Sebaceousgland carcinoma, Secondary neoplasm, Seminoma, Serous tumor,Sertoli-Leydig cell tumor, Sex cord-stromal tumor, Sezary Syndrome,Signet ring cell carcinoma, Skin Cancer, Small blue round cell tumor,Small cell carcinoma, Small Cell Lung Cancer, Small cell lymphoma, Smallintestine cancer, Soft tissue sarcoma, Somatostatinoma, Soot wart,Spinal Cord Tumor, Spinal tumor, Splenic marginal zone lymphoma,Squamous cell carcinoma, Stomach cancer, Superficial spreading melanoma,Supratentorial Primitive Neuroectodermal Tumor, Surfaceepithelial-stromal tumor, Synovial sarcoma, T-cell acute lymphoblasticleukemia, T-cell large granular lymphocyte leukemia, T-cell leukemia,T-cell lymphoma, T-cell prolymphocytic leukemia, Teratoma, Terminallymphatic cancer, Testicular cancer, Thecoma, Throat Cancer, ThymicCarcinoma, Thymoma, Thyroid cancer, Transitional Cell Cancer of RenalPelvis and Ureter, Transitional cell carcinoma, Urachal cancer, Urethralcancer, Urogenital neoplasm, Uterine sarcoma, Uveal melanoma, VaginalCancer Verner Morrison syndrome, Verrucous carcinoma, Visual PathwayGlioma, Vulvar Cancer, Waldenstrom's macroglobulinemia, Warthin's tumor,Wilms' tumor, or any combination thereof.

In some embodiments, said method is for treating a disease selected fromthe group consisting of tumor angiogenesis, chronic inflammatory diseasesuch as rheumatoid arthritis, atherosclerosis, inflammatory boweldisease, skin diseases such as psoriasis, eczema, and scleroderma,diabetes, diabetic retinopathy, retinopathy of prematurity, age-relatedmacular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma andovarian, breast, lung pancreatic, prostate, colon and epidermoid cancer.

In some embodiments, said method is for treating a disease selected frombreast cancer, lung cancer, pancreatic cancer, prostate cancer, coloncancer, ovarian cancer, uterine cancer, cervical cancer, leukemia suchas acute myeloid leukemia (AML), acute lymphocytic leukemia, chroniclymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia,myelodysplasia, myeloproliferative disorders, acute myelogenous leukemia(AML), chronic myelogenous leukemia (CML), mastocytosis, chroniclymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplasticsyndrome (MDS), epidermoid cancer, or hemoglbinopathies such asb-thalassemia and sickle cell disease SCD).

In other embodiments, said method is for treating a disease selectedfrom breast cancer, lung cancer, pancreatic cancer, prostate cancer,colon cancer, ovarian cancer, uterine cancer, or cervical cancer.

In other embodiments, said method is for treating a disease selectedfrom leukemia such as acute myeloid leukemia (AML), acute lymphocyticleukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairycell leukemia, myelodysplasia, myeloproliferative disorders, acutemyelogenous leukemia (AML), chronic myelogenous leukemia (CML),mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM),myelodysplastic syndrome (MDS), epidermoid cancer, or hemoglobinopathiessuch as b-thalassemia and sickle cell disease (SCD).

In yet other embodiments, said method is for treating a disease selectedfrom CCDKN2A deleted cancers, 9P deleted cancers, MTAP deleted cancers,gliobastoma multiforme (GBM), NSCLC, head and neck cancer, bladdercancer, or hepatocellular carcinoma.

Compounds of the disclosure, as well as pharmaceutical compositionscomprising them, can be administered to treat any of the describeddiseases, alone or in combination with a medical therapy. Medicaltherapies include, for example, surgery and radiotherapy (e.g.,gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy,proton therapy, brachytherapy, systemic radioactive isotopes).

In other aspects, compounds of the disclosure, as well as pharmaceuticalcompositions comprising them, can be administered to treat any of thedescribed diseases, alone or in combination with we or more otheragents.

In other methods, the compounds of the disclosure, as well aspharmaceutical compositions comprising them, can be administered incombination with agonists of nuclear receptors agents.

In other methods, the compounds of the disclosure, as well aspharmaceutical compositions comprising them, can be administered incombination with antagonists of nuclear receptors agents.

In other methods, the compounds of the disclosure, as well aspharmaceutical compositions comprising them, can be administered incombination with an anti-proliferative agent.

In other aspects, compounds of the disclosure, as well as pharmaceuticalcompositions comprising them, can be administered to treat any of thedescribed diseases, alone or in combination with one or more otherchemotherapeutic agents. Examples of other chemotherapeutic agentsinclude, for example, abrelix, aldesleukin, alemtuzumab, alitretinoin,allopurinol, all-trans retinoic acid, altretamine, anastrozole, arsenictrioxide, asparaginase, azacitidine, bendamustine, bevacizumab,bexarotene, bleomycin, bortezombi, bortezomib, busulfan intravenous,busulfan oral, calusterone, capecitabine, carboplatin, carmustine,cetuximab, chlorambucil, cisplatin, cladribine, clofarabine,cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparinsodium, dasatinib, daunonrubicin, decitabine, denileukin, denileukin,diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolonepropionate, eculizumab, epirubicin, erlotinib, estramustine, etoposidephosphate, etoposide, exemestane, fentanyl citrate, filgrastim,floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib,gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelinacetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinibmesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate,lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole,lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine,methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone,nandrolone phenpriopionate, nelarabine, nofetumomab, oxaliplatin,paclitaxel, pamidronate, panobinostate, panitumumab, pegaspargase,pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin,procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib,sorafenib, steptozocin, sunitinib, sunitinib maleate, tamoxifen,temozolomide, teniposide, testolactone, thalidomide, thioguanine,thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin,uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine,vorinstat, and zoledronate, as well as any combination thereof.

In other aspects, the other agent is a therapeutic agent that targets anepigenetic regulator. Examples of epigenetic regulator agents include,for example, bromodomain inhibitors, the histone lysinemethyltransferases, histone arginine methyl transferases, histonedemethylases, histone deacetylases, histone acetylases, and DNAmethyltransferases, as well as any combination thereof. Histonedeacetylase inhibitors are preferred in some aspects, and include, forexample, vorinostat.

In other methods wherein the disease to be treated is cancer or anotherproliferative disease, the compounds of the disclosure, as well aspharmaceutical compositions comprising them, can be administered incombination with targeted therapy agents. Targeted therapies include,for example, JAK kinase inhibitors (e.g. Ruxolitinib), PI3 kinaseinhibitors (including PI3K-delta selective and broad spectrum PI3Kinhibitors), MEK inhibitors, Cyclin Dependent kinase inhibitors (e.g.CDK4/6 inhibitors), BRAF inhibitors, mTOR inhibitors, proteasomeinhibitors (e.g., Bortezomib, Carfilzomib), HDAC-inhibitors (e.g.,panobinostat, vorinostate), DNA methyl transferase inhibitors,dexamethasone, bromo and extra terminal family members, BTK inhibitors(e.g., ibrutinib, acalabrutinib), BCL2 inhibitors (e.g., venetoclaz),MCL1 inhibitors, PARP inhibitors, FLT3 inhibitors, and LSDI inhibitors,as well as any combination thereof.

In other methods wherein the disease to be treated is cancer or anotherproliferative disease, the compounds of the disclosure, as well aspharmaceutical compositions comprising them, can be administered incombination with an immune checkpoint inhibitor agents. Immunecheckpoint inhibitors include, for example, inhibitors of PD-1, forexample, an anti-PD-1 monoclonal antibody. Examples of anti-PD-1monoclonal antibodies include, for example, nivolumab, pembrolizumab(also known as MK-3475), pidilizumab, SHR-1210, PDR001, and AMP-224, aswell as combinations thereof. In some aspects, the anti-PD1 antibody isnivolumab. In some aspects, the anti-PD1 antibody pembrolizumab. In someaspects, the immunce checkpoint inhibitor of PD-L1, for example, ananti-PD-L1 monoclonal antibody. In some aspects, the anti-PD-L1monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known asRG7446), or MSB0010718C, or any combination thereof. In some aspects,the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736. In otheraspects, the immune checkpoint inhibitor is an inhibitor of CTLA-4, forexample, and anti-CTLA-4 antibody. In some aspects, the anti-CTLA-4antibody is ipilimumab.

In other methods wherein the disease to be treated is cancer or anotherproliferative disease, the compounds of the disclosure, as well aspharmaceutical compositions comprising them, can be administered incombination with an alkylating agent (e.g., cyclophosphamide (CY),melphalan (MEL), and bendamustine), a proteasome inhibitor agent (e.g.,carfilzomib), a corticosteroid agent (e.g., dexamethasone (DEX)), or animmunomodulatory agent (e.g., lenalidomide (LEN) or pomalidomide (POM)),or any combination thereof.

In some embodiments, the disease to be treated is an autoimmunecondition or an inflammatory condition. In these aspects, the compoundsof the disclosure, as well as pharmaceutical compositions comprisingthem, can be administered in combination with a corticosteroid agentsuch as, for example, triamcinolone, dexamethasone, fluocinolone,cortisone, prednisolone, or flumetholone, or any combination thereof.

In other methods wherein the disease to be treated is an autoimmunecondition or an inflammatory condition, the compounds of the disclosure,as well as pharmaceutical compositions comprising them, can beadministered in combination with an immune suppressant agent such as,for example, fluocinolone acetonide (RETISERT™), rimexolone (AL-2178,VEXOL™, ALCO™), or cyclosporine (RESTASIS™), or any combination thereof.

In some embodiments. the disease to be treated is beta-thalassemia orsickle cell disease. In these aspects, the compounds of the disclosure,as well as pharmaceutical compositions comprising them, can beadministered in combination with one or more agents such as, forexample, HYDREA™ (hydroxyurea).

The examples and preparations provided below further illustrate andexemplify the compounds of the present invention and methods ofpreparing such compounds. It is to be understood that the scope of thepresent invention is not limited in any way by the scope of thefollowing examples and preparations. In the following examples moleculeswith a single chiral center, unless otherwise noted, exist as a racemicmixture. Those molecules with two or more chiral centers, unlessotherwise noted, exist as a racemic mixture of diastereomers. Singleenantiomers/diastereomers may be obtained by methods to those skilled inthe art.

Compounds of the disclosure can be prepared, for example, by referenceto the following schemes

Compounds of the disclosure include, for example, the compoundsidentified in Table A.

TABLE A Example No. Structure MW Chemical Name 1

382.42 (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-1-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-1-hydroxyethyl)tetrahydrofuran- 3,4-diol 2

368.393 (2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3- yl(hydroxy)methyl)tetrahydrofuran-3,4-diol 3

383.408 (2R,3R,4S,5S)-2-(6-amino-9H-purin-9-yl)-5-((R)-1-(bicyclo[4.2.0]octa- 1(6),2,4-trien-3-yl)-1-hydroxyethyl)tetrahydrofuran-3,4- diol 4

400.410403 (2R,3R,4S,5S)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- ((R)-1-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-1- hydroxyethyl)tetrahydrofuran-3,4- diol 5

369.381 (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((R)-bicyclo[4.2.0]octa- 1(6),2,4-trien-3-yl(hydroxy)methyl)tetrahydrofuran- 3,4-diol 6

386.383403 (2R,3R,4S,5R)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)tetrahydrofuran- 3,4-diol 7

382.42 (2S,3S,4R,5R)-2-((R)-1- (bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-1-hydroxyethyl)-5-(6-methyl-9H- purin-9-yl)tetrahydrofuran-3,4-diol8

399.422403 (2S,3S,4R,5R)-2-((R)-1- (bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-1-hydroxyethyl)-5-(5-fIuoro-4- methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol 9

381.432 (2S,3S,4R,5R)-2-((R)-1- (bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-1-hydroxyethyl)-5-(4-methyl-7H- pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol 10

368.393 (2R,3S,4R,5R)-2-((R)- bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-5-(6-methyl-9H- purin-9-yl)tetrahydrofuran-3,4-diol11

367.405 (2R,3S,4R,5R)-2-((R)- bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-5-(4-methyl-7H- pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol 12

385.395403 (2R,3S,4R,5R)-2-((R)- bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-5-(5-fluoro-4- methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol 13

383.404 (2R,3S,4R,5R)-2-((R)-(2,3- dihydrobenzofuran-6-yl)(hydroxy)methyl)-5-(4-methyl-7H- pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol 14

384.392 (2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)- (2,3-dihydrobenzofuran-6-yl)(hydroxy)methyl)tetrahydrofuran- 3,4-diol 15

386.383403 (2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((1R)-(7-fluorobicyclo[4.2.0]octa-1(6),2,4- trien-3-yl)(hydroxy)methyl)tetrahydrofuran- 3,4-diol 16

385.395403 (2R,3S,4R,5R)-2-((1R)-(7- fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)(hydroxy)methyl)-5-(4- methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol 17

404.373806 (2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)- (7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3- yl)(hydroxy)methyl)tetrahydrofuran- 3,4-diol 18

403.385806 (2R,3S,4R,5R)-2-((R)-(7,7-difluorobicyclo[4.2.0]octa-1(6),2,4- trien-3-yl)(hydroxy)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)tetrahydrofuran-3,4-diol 19

382.42 (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3- yl(hydroxy)methyl)-3-methyltetrahydrofuran-3,4-diol 20

398.419 7-((2R,3R,4S,5R)-5-((R)- bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin- 4-one O-methyl oxime 21

412.446 7-((2R,3R,4S,5R)-5-((R)- bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin- 4-one O-ethyl oxime 22

426.473 7-((2R,3R,4S,5S)-5-((R)-1- (bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-1-hydroxyethyl)-3,4- dihydroxytetrahydrofuran-2-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin- 4-one O-ethyl oxime 23

439.472 3-(7-((2R,3R,4S,5R)-5-((R)- bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,1- dimethylurea 24

480.525 N-(7-((2R,3R,4S,5R)-5-((R)- bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperazine-1-carboxamide 25

366.421 (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((S)-bicyclo[4.2.0]octa-1(6),2,4-trien-3- yl(hydroxy)methyl)cyclopentane-1,2-diol 26

380.448 (1R,2S,3R,5S)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((S)-1-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-1-hydroxyethyl)cyclopentane-1,2- diol 27

437.5 3-(7-((1R,2S,3R,4R)-4-((S)- bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-2,3- dihydroxycyclopentyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,1- dimethylurea 28

478.553 N-(7-((1R,2S,3R,4R)-4-((S)- bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-2,3- dihydroxycyclopentyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperazine-1-carboxamide 29

451.527 3-(7-((1R,2S,3R,4S)-4-((S)-1-(bicyclo[4.2.0]octa-1(6),2,4-trien-3- yl)-1-hydroxyethyl)-2,3-dihydroxycyclopentyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1,1-dimethylurea 30

381.43 (2R,3S,4R,5R)-2-((1R)-hydroxy(7-methylbicyclo[4.2.0]octa-1(6),2,4- trien-3-yl)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)tetrahydrofuran-3,4-diol 31

381.39 3-((R)-((2R,3S,4R,5R)-3,4-dihydroxy- 5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-2-yl)(hydroxy)methyl)bicyclo[4.2.0]octa- 1(6),2,4-trien-7-one 32

383.40 (2R,3S,4R,5R)-2-((1R)-hydroxy(7-hydroxybicyclo[4.2.0]octa-1(6),2,4- trien-3-yl)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)tetrahydrofuran-3,4-diol 33

395.46 (2R,3S,4R,5R)-2-((R)-(7,7- dimethylbicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)(hydroxy)methyl)-5-(4- methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol 34

406.44 3-((R)-((2R,3S,4R,5R)-3,4-dihydroxy- 5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-2- yl)(hydroxy)methyl)-7-methylbicyclo[4.2.0]octa-1(6),2,4- triene-7-carbonitrile 35

383.4 (2R,3S,4R,5R)-2-[(R)-4- bicyclo[4.2.0]octa-1,3,5-trienyl(hydroxy)methyl]-5-(4- methoxypyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol 36

447.28 (2R,3R,4S,5R)-2-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-bicyclo[4.2.0]octa-1,3,5-trien-3-yl(hydroxy)methyl)tetrahydrofuran- 3,4-diol 37

494.28 (2R,3R,4S,5R)-2-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3- yl(hydroxy)methyl)tetrahydrofuran-3,4-diol 38

436.38 (2R,3R,4S,5R)-2-(4-amino-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)- bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)tetrahydrofuran- 3,4-diol 39

382.41 (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((S)-1-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-1-hydroxyethyl)tetrahydrofuran- 3,4-diol 40

393.44 (2R,3S,4R,5R)-2-((R)- bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-5-(4-(prop-1-en- 2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol 41

395.45 (2R,3S,4R,5R)-2-((R)- bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-5-(4-isopropyl- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol 42

409.48 (2R,3S,4R,5R)-2-((R)- bicyclo[4.2.0]octa-1,3,5-trien-3-yl(hydroxy)methyl)-5-(4-butyl-7H- pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol 43

383.4 (2R,3S,4R,5R)-2-((R)- bicyclo[4.2.0]octa-1,3,5-trien-3-yl(hydroxy)methyl)-5-(4- (hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4- diol 44

381.43 (2R,3S,4R,5R)-2-((R)-(2,3-dihydro-1H-inden-5-yl)(hydroxy)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)tetrahydrofuran-3,4-diol 45

382.41 (2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)- (2,3-dihydro-1H-inden-5-yl)(hydroxy)methyl)tetrahydrofuran- 3,4-diol 46

379.41 (2R,3S,4R,5R)-2-((R)- bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-5-(4-vinyl-7H- pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol 47

367.4 (2R,3S,4R,5R)-2-((S)- bicyclo[4.2.0]octa-1,3,5-trien-3-yl(hydroxy)methyl)-5-(4-methyl-7H- pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol 48

411.45 (2R,3S,4R,5R)-2-((R)- bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-5-(4-(2- methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4- diol 49

385.39 (2R,3S,4R,5R)-2-((R)- bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-5-(4- (fluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4- diol 50

411.45 (2R,3S,4R,5R)-2-((R)- bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-5-(4- (ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4- diol 51

401.84 (2R,3S,4R,5R)-2-((R)- bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-5-(4- (chloromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4- diol 52

388.44 (2S,3S,4R,5R)-2-((S)-(5,6-dihydro- 4H-cyclopenta[d]thiazol-2-yl)(hydroxy)methyl)-5-(4-methyl-7H- pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol 53

397.42 (2R,3S,4R,5R)-2-((R)- bicyclo[4.2.0]octa-1,3,5-trien-3-yl(hydroxy)methyl)-5-(4-(2- hydroxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4- diol 54

382.41 (2R,3S,4R,5R)-2-((R)- bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-5-(4- (methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4- diol 55

487.55 (2R,3R,4S,5R)-2-(4-(2- (benzyloxy)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)- bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)tetrahydrofuran- 3,4-diol 56

387.82 (2R,3S,4R,5R)-2-((R)- bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-5-(4-chloro-7H- pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol

EXPERIMENTAL PROCEDURES EXAMPLES Example 1(2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-1-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-1-hydroxyethyl)tetrahydrofuran-3,4-diol(1)

Step 1. Synthesis ofbicyclo[4.2.0]octa-1,3,5-trien-3-yl((3aS,4S,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanone(1b)

A 50 mL RBF with septum containing Magnesium (208 mg, 8.56 mmol) wasdried under high vacuum with a heat gun and cooled under Ar. The flaskwas charged with THF (3.4 mL), 4/10ths the portion of4-bromobicyclo[4.2.0]octa-1(6),2,4-triene (1.01 mL, 8.11 mmol), anddiisobutylaluminum hydride, 1M in toluene (20 uL, 0.0200 mmol) at RT.Initiation of the magnesium was observed by self heating of the reactionsolution after 1 minute of stirring. The reaction mixture was stirredfor 10 additional min, diluted with THF (3 mL), then charged with theremaining 4-bromobicyclo[4.2.0]octa-1(6),2,4-triene in two portions over10 min, and stirred at RT for 30 additional min (or until the reactionmixture returns to RT). A majority of the magnesium turnings wereconsumed by the Grignard reagent formation. A solution of 1a,(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-N-methoxy-N,2,2-trimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxole-6-carboxamide(2.21 g, 5.77 mmol) in THF (18 mL) was prepared in a heat-dried RBF. Theketone material was previously exhaustively dried under high vacuum withheat gun to remove a majority of the residual EtOAc solvent. TheGrignard solution was transferred by cannula, dropwise over 2 min, andrinsed with THF (2 mL), to the ketone solution at 0° C. The solution wasstirred at 0° C. for 5 min, then stirred at RT for 30 min. The reactionmixture was cooled to 0° C. in an ice-bath, quenched with EtOAc (1 mL),placed at RT, and stirred for 5 min. The reaction mixture was thenneutralized with sat. NH₄Cl (10 mL), diluted with water (80 mL), andextracted with EtOAc (100 mL). The organic layer was separated, washedwith sat. sodium potassium tartrate (10 mL), water (2×80 mL), brine (40mL), dried over Na₂SO₄ and MgSO₄, filtered, and concentrated to a yellowfoam. The crude mixture was purified by FCC (40 g SiO₂, 0→36% EtOAc inhexanes, wet-loaded in DCM+hexanes) to yield 1b[(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-bicyclo[4.2.0]octa-1(6),2,4-trienyl)methanone(2.32 g, 5.45 mmol, 94.4% yield) as a yellow foam. Rf=0.53 (1:2EtOAc:hexanes); ¹H NMR (600 MHz, Chloroform-d), δ 8.48 (s, 1H), 7.68(dd, J=1.4, 7.7 Hz, 1H), 7.46 (s, 1H), 7.35 (d, J=3.7 Hz, 1H0, 7.05 (dd,J=1.0, 7.6 Hz, 1H), 6.56 (d, J=3.7 Hz, 1H), 6.45 (d, J=1.3 Hz, 1H), 5.61(dd, J=2.1, 6.1 Hz, 1H), 5.48 (d, J=2.1 Hz, 1H), 5.42 (dd, J=1.3, 6.0Hz, 1H), 3.21-3.14 (m, 4H), 1.70 (s, 3H), 1.44 (s, 3H); LRMS (ESI) m/zcalcd for [M+H]⁺ C₂₂H₂₁ClN₃O₄: 426.12/426.12. Found: 426.0/428.0.

Step 2. Synthesis of(R)-1-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-1-((3aS,4S,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)ethan-1-ol(1c and 1d)

A 25 mL RBF with septum containing 1b,[(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)methanone(442.5 mg, 1.04 mmol) was evacuated and backfilled with Ar (>3). Theflask was charged with THF (6 mL), placed in a RT water bath, andcharged with methyl magnesium bromide, 3.2 M in MeTHF (0.81 mL, 2.6mmol), dropwise over 10 min. The reaction was stirred at RT for 1 h.Reaction complete by TLC and LCMS, showing a ˜5:1 ratio of diastereomersby LCMS. The reaction mixture was carefully quenched with sat. NH₄Cl (2mL) (caution: gas evolution), diluted with water (40 mL), extracted withEtOAc (40 mL), washed with water (40 mL), brine (20 mL), and dried overNa₂SO₄. The mixture was filtered, concentrated under reduced pressure,and purified by FCC (40 g, SiO₂, 0→30% EtOAc in hexanes, wet-loaded inDCM). to yield 1c(1R)-[(3aR,4R,6S,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)ethanol(349.7 mg, 0.7913 mmol, 76.2% yield) as a white foam and 1d(1S)-1-[(3aR,4R,6S,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)ethanol(4.6 mg, 0.105 mmol, 10.1% yield) as a clear pink glass.

-   (1c) Rf=0.58 (1:2 EtOAc:hexanes); ¹H NMR (600 MHz, Chloroform-d), δ    9.74 (s, 1H), 7.41 (dd, J=1.5, 7.7 Hz, 1H), 7.35 (d, J=3.7 Hz, 1H),    7.27 (s, 1H), 7.09 (d, J=7.7 Hz, 1H), 6.66 (d, J=3.7 Hz, 1H), 6.38    (bs, 1H), 5.85 (d, J=5.5 Hz, 1H), 5.17 (t, J=5.7 Hz, 1H), 4.72 (dd,    J=1.2, 6.0 Hz, 1H), 4.64 (d, J=1.2 Hz, 1H), 3.23-3.16 (m, 4H), 1.58    (s, 3H), 1.51 (s, 3H), 1.21 (s, 3H); LRMS (ESI) m/z calcd for [M+H]⁺    C₂₃H₂₅ClN₃O₄: 442.15/444.15. Found: 442.0/444.0.-   (1d) Rf=0.48 (1.2 EtOAc:hexanes); ¹H NMR (400 MHz, Chloroform-d), δ    8.73 (dd, J=2.4, 6.8 Hz, 1H), 7.29-7.25 (m, 1H), 7.22 (bs, 1H), 7.17    (d, J=3.7 Hz, 1H), 7.13 (s, 1H), 6.95 (d, J=7.7 Hz, 1H), 6.54 (d,    J=3.6 Hz, 1H), 5.75 (d, J=4.6 Hz, 1H), 5.31 (dd, J=2.4, 6.5 Hz, 1H),    5.14 (dd, J=4.6, 6.7 Hz, 1H), 4.71 (d, J=2.4 Hz, 1H), 3.12-3.03 (m,    4H), 1.66 (s, 3H), 1.61 (s, 3H), 1.41 (s, 3H), LRMS (ESI) m/z calcd    for [M+H]⁺ C₂₃H₂₅ClN₃O₄: 442.15/444.15. Found: 442.1/444.1.

Step 3. Synthesis of(R)-1-((3aR,4S,6R,6aR)-6-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-1-bicyclo[4.2.0]octa-1,3,5-trien-3-yl)ethan-1-ol(1e)

A 5 mL microwave vial with septum containing 1c(1R)-1-[(3aR,4S,6R,6aR)-4-(4chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-1-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)ethanol(132.5 mg, 0.300 mmol) was evacuated and backfilled with Ar (×3). Thevial was charged with 1,4-Dioxane (1 mL) and ammonium hydroxide (2 mL,30 mmol), and briefly heated until a homogeneous solution formed. Thereaction mixture was then microwaved at 120° C. for 12 h. The mixturewas concentrated under reduced pressure to remove all volatiles and usedcrude in the next reaction. LRMS (ESI) m/z calcd for [M+H]⁺ C₁₃H₂₇N₃O₄:423.20. Found: 423.1.

Step 4. Synthesis of(2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-1-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-1-hydroxyethyl)tetrahydrofuran-3,4-diol(Ex. 1)

A 100 mL RBF with septum containing a solution of crude 1e((1R)-1-[(3aR,4S,6S,6aR)-4-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-1-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)ethanol)(0.30 mmol) in Methanol (2 mL) was purged with Ar for 1 min. thereaction mixture was charged with Hydrochloric acid, 1M (2 mL, 2 mmol)and stirred at RT for 2 h. The reaction mixture was then charged withHydrochloric acid, 1M (2 mL, 2 mmol) and stirred for RT for 2 h. Themixture was concentrated under reduced pressure and purified by FCC (30g C18, 5→40% MeCN in H₂O, wet-loaded in DMSO). One fraction containingproduct was lyophilized to yield the TFA salt of Ex. 1.(2R,3R,4S,5S)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5[(1R)-1-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)-1-hydroxy-ethyl]tetrahydrofuran-3,4-diol;2,2,2-trifluoroacetic acid (34.4 mg, 93.8% purity, 0.0650 mmol, 21.7%yield over two steps), as a fluffy white solid. Another fractioncontaining product was concentrated under reduced pressure, diluted withMeOH, neutralized with Amberlite IRA-67 resin, filtered through acellulose acetate frit, and concentrated under reduced pressure and heat(50° C.) to yield Ex. 1(2R,3R,4S,5S)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R)-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)-1-hydroxy-ethyl]tetrahydrofuran-3,4-diol(51.2 mg, 95.5% purity, 0.128 mmol, 42.6% yield over two steps) as abeige powder.

(TFA salt of Ex. 1) ¹H NMR (400 MHz, DMSO-d₆), δ 9.23-8.00 (m, 3H), 8.36(s, 1H), 7.75 (d, J=3.6 Hz, 1H), 7.37 (dd, J=1.5, 7.8 Hz, 1H), 7.24 (s,1H), 7.05 (d, J=7.7 Hz, 1H), 6.94 (d, J=3.4 Hz, 1H), 6.05 (d, J=8.0 Hz,1H), 5.86 (bs, 1H), 5.19 (bs, 1H), 4.87 (bs, 1H), 4.47 (dd, J=5.0, 7.9Hz, 1H), 4.09 (s, 1H), 3.73 (d, J=5.0 Hz, 1H), 3.12 (s, 4H), 1.41 (s,3H); LRMS (ESI) m/z calcd for [M+H]⁺ C₂₀H₂₃N₄O₄: 383.17 Found: 383.1.

(Ex. 1) ¹H NMR (400 MHz, DMSO-d₆), δ 8.09 (s, 1H), 7.39 (dd, J=1.4, 7.8Hz, 1H), 7.36 (d, J=3.6 Hz, 1H), 7.29 (bs, 2H), 7.25 (s, 1H), 7.04 (d,J=7.7 Hz, 1H), 6.86 (bs, 1H), 6.61 (d, J=3.6 Hz, 1H), 5.81 (d, J=8.1 Hz,1H), 5.12 (d, J=7.2 Hz, 1H), 4.72 (d, J=3.5 Hz, 1H), 4.65 (td, J=5.0,7.6 Hz, 1H), 4.11 (s, 1H), 3.68 (dd, J=3.2, 5.0 Hz, 1H), 3.12 (s, 4H),1.37 (s, 3H), LRMS (ESI) m/z calcd for [M+H]⁺ C₂₀H₂₃N₄O₄: 383.17. Found:383.1.

Example 2(2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)tetrahydrofuran-3,4-diol(2)

Step 1. Synthesis of(R)-bicyclo[4.2.0]octa-1,3,5-trien-3-yl((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanone(2a) and(R)-bicyclo[4.2.0]octa-1,3,5-trien-3-yl((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(2b)

A 100 mL RBF with septum containing a solution of[(3aR,4R,6s,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-4-bicyclo[4.2.0]octa-1,3,5-trienyl)methanone(1200 mg, 2.82 mmol) in toluene (25 mL) under argon was cooled to −76°C. in a acetone/dry-ice bath. Diisobutylaluminum hydride; DIBAL, 1M intoluene (5.4 mL, 5.4 mmol) was added dropwise over 4 min. The reactionmixture was stirred at −76° C. for 1 h and TLC (hexane/EtOAc 70:30)showed completion. The reaction was placed in a 0° C. ice bath andquenched with the careful addition of water (0.04×5.4 mL), 15% NaOH(0.04×5.4 mL) and water (0.1×5.4 mL) of water and stirred for 15 min.The reaction mixture was charged with Na₂SO₄, stirred for another 5 minand filtered through a pad of celite. The crude was concentrated underreduced pressure and purified on a 40 g silica gel column chromatographyusing hexane/EtOAc to give(R)-1-((3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl)-4-bicyclo[4.2.0]octa-1,3,5-trienyl)methanol(2a) (800 mg, 1.87 mmol, 66.4% yield) and(S)-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-4-bicyclo[4.2.0]octa-1,3,5-trienyl)methanol(2b) (370 mg, 0.86 mmol, 30.7% yield) as white solids.

For compound 2a ¹H NMR (400 MHz, Chloroform-d), δ 8.71 (s, 1H), 7.35 (d,J=3.7 Hz, 1H), 7.30 (dd, J=1.3, 7.8 Hz, 1H), 7.18 (d, J=1.2 Hz, 1H),7.09-7.05 (m, 1H), 6.65 (d, J=3.7 Hz, 1H), 5.86 (d, J=5.2 Hz, 1H), 5.26(t, J=5.6 Hz, 1H), 5.08 (d, J=2.0 Hz, 1H), 5.02 (dd, J=1.4, 6.1 Hz, 1H),4.59 (t, J=1.8 Hz, 1H), 3.18 (s, 4H), 1.58 (s, 3H), 1.29 (s, 3H).

Step 2. Synthesis of(R)-((3aR,4R,6R,6aR)-6-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)methanol(2c)

To(R)-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-4-bicyclo[4.2.0]octa-1,3,5-trienyl)methanol(600 mg, 1.4 mmol) in Methanol (5 mL) was added the ammonium hydroxide(1 mL, 2.8 mmol). The reaction was heated at 120° C. for 16 h. Thereaction mixture was concentrated and the crude was extracted with ethylacetate, washed with water, brine, dried over sodium sulfate, filteredand concentrated. The crude was purified by silica gel chromatographyusing 0-30% EtOAc in DCM to give(R)-[(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)methanol(2c) 320 mg 0.78 mmol, 55.9% yield) and(R)-[(3aR,4R,6R,6aR)-4-(4-methoxypyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-4-bicyclo[4.2.0]octa-1,3,5-trienyl)methanol(140 mg, 0.33 mmol, 23.6% yield).

Step 3. Synthesis of(2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)tetrahydrofuran-3,4-diol(2)

To a stirred solution of crude(R)-[(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-4-bicyclo[4.2.0]octa-1,3,5-trienyl)methanol(122 mg, 0.300 mmol) in Methanol (2 mL) was added Hydrochloric acid, 1 M(4 mL, 4 mmol) and the reaction was stirred for 4 h at rt. LCMS showedcompletion and the reaction was cooled to 0° C. and neutralized by thecareful addition of Amberlite IRA-67. The reaction was filtered throughfilter paper and concentrated under reduced pressure. The crude wasdried loaded on celite and purified on a silica gel columnchromatography using CH₂Cl₂/CH₂Cl₂:MeOH 20% to give(2R,3R,4S,5R)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(R)4-bicyclo[4.2.0]octa-1,3,5-trienyl(hydroxy)methyl]tetrahydrofuran-3,4-diol(Ex 2) (70 mg, 0.18 mmol, 59% yield) as a white solid. ¹H NMR (400 MHz,Methanol-d4 ), δ 8.09 (s, 1H), 7.33-7.24 (m, 1H), 7.21 (d, J=3.7 Hz,1H), 7.17 (s, 1H), 7.03 (d, J=7.6 Hz, 1H), 6.60 (d, J=3.6 Hz, 1H), 5.89(d, J=7.6 Hz, 1H), 4.97 (d, J=2.4 Hz, 1H), 4.81 (dd, J=5.2, 7.7 Hz, 1H),4.25 (s, 1H), 4.24-4.23 (m, 1H), 3.17 (s, 4H). LCMS: [M+H] 369.0.

Example 6(2R,3R,4S,5R)-2-(4-amino-5-fluoro-pyrrolo[2,3-d]pyrimidin-7-yl)-5-[(R)-4-bicyclo[4.2.0]octa-1,3,5-trienyl(hydroxy)methyl]tetrahydrofuran-3,4-diolhydrochloride (Ex. 6)

a) Synthesis of(S)-[(3aR,4R,6R,6aR)-4-methoxy-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-4-bicyclo[4.2.0]octa-1,3,5-trienyl)methanol(6a)

To a solution of 4-bicyclo[4.2.0]octa-1,3,5-trienylboronic acid (3500.0mg, 23.65 mmol) in Toluene (90 mL), Diethylzinc (23.74 mL, 47.48 mmol)was added slowly at 25° C. The mixture was stirred at 60° C. for 1 hrs.(3aR,4R,6R,6aR)-4methoxy-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxole-6-carbaldehyde(3200.0 mg, 15.83 mmol) in Toluene (40 mL) was added slowly at 60° C.The mixture was stirred at 60° C. for 2 hrs. TLC (PE/EA=5/1) showed thereaction was completed. Water (10 ml) was added to quench the reaction.The mixture was filtered. The filtrate was concentrated and purified bycombi-flash eluting with CH₃CN/H₂O (neutral condition) from 5/95 to85/15 to give(S)-[(3aR,4R,6R,6aR)-4-methoxy-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-4-bicyclo[4.2.0]octa-1,3,5-trienyl)methanol(6a) (2900 mg, 9.466 mmol, 55.8% yield) as a white solid.

b) Synthesis of[(R)-[(3aR,4R,6R,6aR)-4-methoxy-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-4-bicyclo[4.2.0]octa-1,3,5-trienyl)methyl]4-phenylbenzoate(6b)

To a mixture of(S)-[(3aR,4R,6R,6aR)-4-methoxy-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-4-bicyclo[4.2.0]octa-1,3,5-trienyl)methanol(6a) (2900 mg, 9.47 mmol), 4-phenylbenzoic acid (2815 mg, 14.2 mmol) andTriphenylphosphine (3724 mg, 14.2 mmol) in Toluene (50 mL), DIAD (2.8mL, 14.2 mmol) was added at 0° C. The mixture was stirred at 25° C. for3 hrs. The mixture was concentrated and purified by combi-flash elutingwith CH₃CN/H₂O (neutral) from 5/95 to 95/5 to give[(R)-[(3aR,4R,6R,6aR)-4-methoxy-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-4-bicyclo[4.2.0]octa-1,3,5-trienyl)methyl]4-phenylbenzoate(6b) (3700 mg, 7.604 mmol, 80.33% yield) as a white solid.

c) Synthesis of[(R)-4-bicyclo[4.2.0]octa-1,3,5-trienyl-[(2S,4R,3S,6R)-3,4,5-trihydroxytetrahydrofuran-2-yl]methyl]4-phenylbenzoate (6c)

A mixture of[(R)-1-[(3aR,4R,6R,6aR)-4-methoxy-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)methyl]4-phenylbenzoate(6b) (2421.41 mg, 4.98 mmol) in water (30.0 mL, 1664.8 mmol) and TFA(30.0 mL, 405.19 mmol) was heated to 40° C. and stirred for 36 h. TLC(PE/EA=1/1, Rf=0.3) showed the desired product. The mixture wasconcentrated and purified by purified by combi-flash eluting withCH₃CN/H₂O (neutral) from 5/95 to 95/5 to give[(R)-4-bicyclo[4.2.0]octa-1,3,5-trienyl-[(2S,3S,4R)-3,4,5-trihydroxytetrahydrofuran-2-yl]methyl]4-phenylbenzoate(6c) (1600 mg, 3.700 mmol, 74.34% yield) as white solid.

d) Synthesis of[(R)-4-bicyclo[4.2.0]octa-1,3,5-trienyl-[(2S,3S,4R,5R)-5-fluoro-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl]4-phenylbenzoate(6d)

To a solution of 4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (79.34mg, 0.46 mmol) in dry THF (10 mL) was added Pyridine (0.04 mL, 0.46mmol). Then Tributylphosphane (0.23 mL, 0.92 mmol) and DIAD (0.2 mL,1.02 mmol) was added at 25° C.,[(R)-4-bicyclo[4.2.0]octa-1,3,5-trienyl-[(2S,3S,4R)-5-3,4,5-trihydroxytetrahydrofuran-2-yl]methyl]4-phenylbenzoate(6c) (200.0 mg, 0.46 mmol) in dry THF (5 mL) was added at once. Thereaction mixture was stirred at 25° C. for 2 h. The reaction mixture waspurified by reversed-phase combi-flash (neutral condition) eluting withH₂O:CH₃CN from 90:10 to 5:95 to[(R)-4-bicyclo[4.2.0]octa-1,3,5-trienyl-[(2S,3S,4R,5R)-5-(4-chloro-5-fluoro-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl]4-phenylbenzoate(6d) (111 mg, 0.189 mmol, 41.0% yield) as a pale yellow solid.

e) Synthesis of(2S,3S,4R,5R)-2-(4-amino-5-fluoro-pyrrolo[2,3-d]pyrimidin-7-yl)-5-[(R)-4-bicyclo[4.2.0]octa-1,3,5-trienyl(hydroxy)methyl]tetrahydrofuran-3,4-diolhydrochloride (Ex. 6)

To a mixture of[(R)-4-bicyclo[4.2.0]octa-1,3,5-trienyl[2S,3S,4R,5R)-5-(4-chloro-5-fluoro-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl]4-phenylbenzoate(6d) (111.0 mg, 0.19 mmol) in 1,4-Dioxane (3 mL). Ammonium hydroxide(3.0 mL, 77.89 mmol) was added. The mixture was stirred at 120° C. for16 hrs. LCMS (SYZ003-81-R1) showed the reaction has been completed. Themixture was concentrated and purified by prep-HPLC eluting withCH₃CN/H₂O (0.1% TFA) from 5/95 to 95/5 to give the solution of desiredproduct which was added 2M HCl (4 mL) and lyophilizated to give(2R,3R,4S,5R)-2-(4-amino-5-fluoropyrrolo[2,3-d]pyrimidin-7-yl)-5-[(R)-4-bicyclo[4.2.0]octa-1,3,5-trienyl(hydroxy)methyl]tetrahydrofuran-3,4-diolhydrochloride (Ex. 6) (24.9 mg, 0.056 mmol, 69.7% yield) as a whitesolid. ¹H NMR and ¹⁹F NMR verified the product. ¹H NMR (400 M Hz,DMSO-d6), δ 8.65 (brs, 2H), 8.35 (s, 1 H), 7.63 (s, 1 H), 7.20 (d, J=7.6Hz, 1 H), 7.10 (s, 1 H), 7.01 (d, J=7.6 Hz, 1 H), 6.11 (d, J=7.2 Hz, 1H), 4.71 (d, J=4.8 Hz, 1 H), 4.39-4.43 (m, 1 H), 4.09 (d, J=4.8 Hz, 1H), 3.99 (d, J=4.4 Hz, 1 H), 3.09 (s, 4 H). ¹H NMR (400 MHz,DMSO-d6+D₂), δ 8.33 (s, 1 H), 7.60 (d, J=1.6 Hz, 1 H), 7.20 (d, J=7.6Hz, 1 H), 7.10 (s, 1 H), 7.02 (d, J=7.6 Hz, 1 H), 6.12 (d, J=7.6 Hz, 1H), 4.71 (d, J=4.8 Hz, 1 H), 4.39-4.43 (m, 1 H), 4.10 (d, J=5.2 Hz, 1H), 4.01 (d, J=4.8 Hz, 1 H), 3.10 (s, 4H). 19F NMR (376 M Hz, DMSO-d6):δ −164.51 (s, 1 F).

Example 112R,3S,4R,5R)-2-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol(11)

Step 1. Synthesize of[(R)-[3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxo-6-yl]-(4-bicyclo[4.2.0]octa-1(6),2,4-trienyl)methanol]benzoate(11a)

Isopropyl (NE)-N-isopropoxycarbonyliminocarbamate (0.31 mL, 1.55 mmol)was added dropwise to a solution of(S)-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-bicyclo[4.2.0]octa-1(6),2,4-trienyl)methanol(2b) (368 mg, 0.86 mmol) and triphenylphosphine (345 mg, 1.29 mmol) inTHF (5 mL) at RT. The reaction became warm. The reaction mixture wasstirred at RT overnight. TLC (3:1 Hexane:EA) showed 2b was consumed. Thereaction was concentrated under vacuum and the crude product waspurified on a 20 g column to give[(R)[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-4-bicyclo[4.2.0]octa-1,3,5-trienyl)methyl]benzoate(11a) (290 mg, 0.545 mmol, 63.4% yield) as a white foamy solid.

Step 2. Synthesis of(R)-bicyclo[4.2.0]octa-1,3,5-trien-3-yl((3aR,4R,6R,6aR)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuro[3,4-d][1,3]-4-yl)methylbenzoate (11b)

A 100 mL RBF with septum containing[(R)-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxo-6-yl]-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)methyl]benzoate(272 mg, 0.51 mmol) and palladium; triphenylphosphane (30 mg, 0.030mmol) under Ar was charged with THF (4 mL) and purged with Ar for 1 min(bright yellow sol'n). The vial was then charged with Dimethylzinc (1.0mL, 2.0 mmol) (extreme care to avoid contact with air, pull back onsyringe to fill needle volume with Ar/N2 before transferring betweenvessels, excess/residual reagent in syringe was diluted in test tubecontaining hexanes and let quench by air), and heated at 70° C. for 2.5h. Complete by LCMS analysis. The reaction mixture was quenched bydropwise addition of sat. NaHCO₃ (2 mL) at rt under Ar with vigorousstirring. The reaction mixture was diluted with EtOAc (30 mL) and vacuumfiltered through a cellulose acetate filter. The salts were vigorouslyrinsed with water (20 mL) and EtOAc (20 mL). The filtrate was dilutedwith water (30 mL) and extracted with EtOAc (50 mL). The organicfraction was washed with water (70 mL), brine (40 mL), dried overHa₂SO₄, and filtered. The filtrate was concentrated under reducedpressure and purified by FCC (20 g SiO₂, 0→60% EtOAc in hexanes,wet-loaded in DCM). Fractions containing product were combined andconcentrated under reduced pressure and heat (50° C.) to yield[(R)-[(3aR,4R,6R,6aR)-2,2-dimethyl-4-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)methyl]benzoate(197 mg, 0.381 mmol, 74.6% yield) as a yellow foam/gum. Rf=0.55 (2.1EtOAc:hexanes). LCMS Found: 512.1. ¹H NMR (400 MHz, Chloroform-6) δ 8.72(s, 1H), 8.02-7.94 (m, 2H), 7.55 (tt, J=1.4, 7.5 Hz, 1H), 7.39 (tt,J=1.3, 7.6 Hz, 2H), 7.10 (d, J=3.7 Hz, 1H), 7.08-7.01 (m, 1H), 6.97-6.91(m, 2H), 6.46 (d, J=3.7 Hz, 1H), 6.23 (d, J=2.6 Hz, 1H), 6.19 (d, J=5.9Hz, 1H), 5.49 (dd, J=2.6, 6.4 Hz, 1H), 5.21 (dd, J=3.0, 6.4 Hz, 1H),4.68 (dd, J=3.0, 5.9 Hz, 1H), 3.13-3.04 (m, 4H), 2.67 (s, 3H), 1.63 (s,3H), 1.40 (s, 3H).

Step 3. Synthesis of(R)-bicyclo[4.2.0]octa-1,3,5-trien-3-yl((3aR,4R,6R,6aR)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuro[3,4-d][1,3]-4-yl)methanol(11c) (11b)

A 100 mL RBF containing a solution of[(R)-[(3aR,4R,6R,6aR)-2,2-dimethyl-4-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)methyl]benzoate(11b) (197 mg, 0.39 mmol) in Methanol (3 mL) was purged with Ar for 2min. The solution was charged with sodium methoxide, 0.5 M in MeOH (2mL, 1 mmol) and stirred at RT for 3 d. The reaction mixture wasneutralized with NH₃Cl (20 mL), diluted with water (30 mL), andextracted with EtOAc (50 mL). The organic fraction was washed with brine(25 mL), dried over Na₂SO₄, filtered, and concentrated under reducepressure and heat (50° C.) to give 257 mg crude product (11c) Rf=0.51(2:1 EtOAc:hexanes). LCMS [M+H] 408.1

Step 4. Synthesis of(2R,3S,4R,5R)-2-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol(11)

A 100 mL RBF with septum containing(R)-[(3aR,4R,6R,6aR)-2,2-dimethyl-4-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)methanol(11c) (156.9 mg, 0.39 mmol) under Ar was charged with Methanol (3 mL).The solution was purged with Ar for 1 min, then charged with 1 MHydrochloric acid (aq) (3 mL, 3 mmol) and stirred at RT for 16 h. Thereaction mixture was quenched with sat. sodium bicarbonate (3 mL), thendiluted with water (20 mL) and brine (40 mL). The mixture was extractedwith DCM (2×50 mL) then 20% MeOH in DCM (2×50 mL). The organic fractionswere combined, dried over Na₂SO₄, filtered, and purified by FCC (20 gSiO₂0→8% MeOH in DCM, wet-loaded in DCM). Fractions containing pureproduct were combined and concentrated under reduced pressure and heat(50° C.) to yield(2R,3S,4R,5R)-2-[(R)-4-bicyclo[4.2.0]octa-1,3,5-trienyl(hydroxy)methyl]-5-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol(Ex 11) (150 mg, 100% yield) as a white foam/powder. Crystalline undermicroscope. ¹H NMR (400 MHz, DMSO-d6), δ 8.65 (s, 1H), 7.77 (d, J=3.8Hz, 1H), 7.21 (dd, J=1.3, 7.6 Hz, 1H), 7.10 (s, 1H), 7.00 (d, J=7.5 Hz,1H), 6.78 (d, J=3.7 Hz, 1H), 6.14 (d, J=7.8 Hz, 1H), 5.96 (d, J=4.1 Hz,1H), 5.26 (d, J=7.0 Hz, 1H), 5.07 (d, J=4.0 Hz, 1H), 4.74 (t, J=4.5 Hz,1H) 4.58 (td, J=5.0, 7.5 Hz, 1H), 4.10 (t, J=4.6 Hz, 1H), 4.00 (d, J=4.7Hz, 1H), 3.08 (s, 4H), 2.66 (s, 3H). ¹H NMR (400 MHz, DMSO-d6+D2O), δ8.58 (s, 1H), 7.62 (t, J=4.1 Hz, 1H), 7.14 (d, J=7.6 Hz, 1H), 7.03 (s,1H), 6.97 (d, J=7.6 Hz, 1H), 6.77 (d, J=2.2 Hz, 1H), 6.10-6.04 (m, 1H),4.68 (d, J=4.7 Hz, 1H), 4.54 (dd, J=5.2, 7.6 Hz, 1H), 4.02 (d, J=4.9 Hz,1H), 3.03 (s, 4H), 2.63 (s, 3H), LCMS [M+H]: 368.1

Example 207-((2R,3R,4S,5R)-5-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-3,4-dihdyroxytetrahydrofuran-2-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-oneO-methyl oxime (20)

Step 1. Synthesis of(R)-[(3aR,4R,6R,6aR)-4-[(4E)-4-methoxyimino-1H-pyrrolo[2,3-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)methanol(20a)

To(R)-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-yl]-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)methanol(2a) (138 mg, 0.320 mmol) in 1-Butanol (2.7 mL) was addedN-ethyl-N-isopropyl-propan-2-amine (0.40 mL., 2.26 mmol), andO-Methylhydroxylamine hydrochloride (135 mg, 1.61 mmol). The reactionwas heated at 120° C. After 24 h LCMS showed 1:1 ratio of startingmaterial and product. Another portion of O-Methylhydroxylaminehydrochloride (135 mg, 1.61 mmol) and N-ethyl-N-isopropyl-propan-2-amine(0.40 mL, 2.26 mmol) were added and the reaction was stirred for further16 h at 120° C. LCMS showed almost completion and the reaction wasconcentrated under reduced pressure, dissolved in EtOAc and washed withwater. The aqueous was back extracted with EtOAc and the combinedorganic layers were washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure. The crude was purified on a 12 gsilica gel column chromatography using EtOAc in CH₂Cl₂ (first 1 min onlyDCM followed by ramp up for 11 min until 40% of EtOAc and 5 min at 40%)to give 11 mg of recovered starting material and(R)-[(3aR,4R,6R,6aR)-4-[(4E)-4-methoxyimino-1H-pyrrolo[2,3-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)methanol(20a) (50 mg, 0.11 mmol, 35% yield)

Step 2. Synthesis of7-((2R,3R,4S,5R)-5-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]primidin-4-oneO-ethyl oxime (20)

To a 100 mL RBF with septum containing a solution of(R)[(3aR,4R,6R,6aR)-4-[3-[(Z)-methoxyiminomethyl]pyrrol-1-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)methanol(20a) (40 mg, 0.90 mmol) in Methanol (0.70 mL) was added Hydrochloricacid, 1M (1.4 mL, 1.4 mmol) dropwise and the reaction mixture wasstirred at rt for 4 h. The reaction was cooled to 0° C. (ice bath)neutralized with aqueous NaHCO₃, concentrated under reduced pressure andextracted with CH₂Cl₂. The organic layer was dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The crude waspurified on a 4 g silica gel column chromatography usingCH₂Cl₂/CH₂Cl₂:MeOH 20% (1 min only CH₂Cl₂ then ramp up for 7 min with50% of solvent B) to give(2R,3R,4S,5R)-2-[(R)-4-bicyclo[4.2.0]octa-1,3,5-trienyl(hydroxy)methyl]-5-[(4Z)-4-methoxyimino-1H-pyrrolo[2,3-d]pyrimidin-7-yl]tetrahydrofuran-3,4-diol(Ex 20) (12.9 mg, 0.0323 mmol, 38.0% yield) as a white solid. ¹H NMR(400 MHz, Methanol-d₄) δ 8.38 (br s, 1H), 7.57 (br s, 1H), 7.26 (d,J=7.6 Hz, 1H), 7.14 (s, 1H), 7.02 (d, J=7.7 Hz, 1H), 6.43 (br s, 1H),5.87 (br s, 1H), 4.93 (d, J=2.9 Hz, 1H), 4.65 (br, 1H), 4.22 (m, 2H),3.83 (s, 3H), 3.15 (s, 4H), LCMS [M+H]: 399.04

Example 217-((2R,3R,4S,5R)-5-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-oneO-ethyl oxime (21)

Example 21 was prepared via similar procedures to those of preparing Ex20 except for substituting O-Methylhydroxylamine hydrochloride withO-Ethylhydroxylamine hydrochloride ¹H NMR (400 MHz, Methanol-d4)(possible tautomers) δ 8.19 (br s, 1H), 7.58 (s, 1H), 7.28-7.04 (m, 3H),6.66 (br s, 0.4H), 6.42 (br s, 0.6H), 5.9 (br s, 0.4 H), 5.85 (d, J=7.6Hz, 0.6H), 4.9 (br s, 1H), 4.82 (br s, 0.4H), 4.64 (br s, 0.6H), 4.25(m, 2H), 4.07 (q, J=7.2 Hz, 2H), 3.18 (s, 4H), 1.35 (m, 3H). LCMS [M+H]:413.1

Example 227-((2R,3R,4S,5R)-5-((R)-1-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-1-hydroxyethyl)-3,4-dihydroxytetrahydrofuran-2-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-oneO-ethyl oxime (22)

Step 1. Synthesis of7-((3aR,4R,6R,6aR)-6-((R)-1-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-1-hydroxyethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-oneO-ethyl oxime (22a)

To(1)-1-[(3aR,4R,6S,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-1-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)methanol(1c) (210 mg, 0.48 mmol) in 1-Butanol (4 mL) was addedethoxyaminehydrochloride (239 mg, 2.38 mmol), andN-ethyl-N-isopropyl-propan-2-amine (0.59 mL, 3.33 mmol). The reactionwas heated at 120° C. for 16 h. The reaction mixture was concentratedand the crude was extracted with ethyl acetate, washed with water,brine, dried over sodium sulfate, filtered and concentrated. The crudewas purified by silica gel chromatography using 0-30% EtOAc in DCM togive 125 mg of the acetal oxime product (22a).

Step 2. Synthesis of7-((2R,3R,4S,5S)-5-((R)-1-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-1-hydroxyethyl)-3,4-dihydroxytetrahydrofuran-2-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-oneO-ethyl oxime (22)

The acetal 22a was dissolved in 2 mL of methanol and treated with 2 mLof 1N HCl and stirred for 16 h. The reaction mixture was cooled in anice water bath and treated with dropwise addition of saturated sodiumbicarbonate to pH 8. The reaction was extracted with ethyl acetate,washed with water, brine, dried over sodium sulfate, filtered andconcentrated. The crude was purified by silica gel chromatography using0-10% methanol in DCM on a 12 g Agela column to give(2R,3S,4R,5R)-2-[(1R)-1-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)-1-hydroxy-ethyl]-5-[4-(ethoxyamino)pyrrolo[2,3-d]pyrimidin-7-yl]tetrahydrofuran-3,4-diol(Ex 22) (94 mg, 0.22 mmol, 46% yield). ¹H NMR (400 MHz, Methanol-d4)(possible tautomers) δ 8.22 (br s, 1H), 7.60 (s, 0.6H), 7.39-7.13 (m,3.4H), 6.64 (br s, 0.4H), 6.40 (d, J=3.4 Hz, 0.6H), 5.87 (d, J=8.0,0.4H), 5.75 (d, J=8.0 Hz, 0.6H), 4.83 (m, 0.4H), 4.64 (m, 0.6H),4.29-4.25 (m, 1H), 4.05 (q, J=7.0 Hz, 2H), 3.92 (m, 1H), 3.16 (s, 4H),1.51 (s, 3H), 1.33 (m, 3H).

Example 233-[7-[(2R,3R,4S,5R)-5-[(R)-4-bicyclo[4.2.0]octa-1,3,5-trienyl(hydroxy)methyl]-3,4-dihydroxy-tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-4-yl]-1,1-dimethyl-urea(Ex. 23)

a) Synthesis of[(R)-[(3aR,4R,6S,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuran[3,4-d][1,3]dioxol-6-yl]-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)methoxy]-triethyl-silane(23a)

To a solution of(R)-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)methanol(2a) (400.0 mg, 0.93 mmol) and Imidazole (636.44 mg, 9.35 mmol) in DMF(5 mL) was added TESCI (704.5 mg, 4.67 mmol), the reaction mixture wasstirred at 25° C. for 18 h. LCMS showed the reaction was completed andthe desired product was the main peak. The reaction mixture was purifiedby reversed-phase combi-flash (neutral condition) eluting with H₂O:CH₃CNfrom 40:60 to 0:100 to give[(R)-[(3aR,4R,6S,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)methoxy]-triethyl-silane(23a) (484 mg, 0.8749 mmol, 93.588% yield) as an oil.

b)3-[7-[(3aR,4R,6S,6aR)-6-[(R)-4-bicyclo[4.2.0]octa-1,3,5-trienyl(triethylsilyloxy)methyl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidin-4-yl]-1,1-dimethyl-urea(23b)

To a solution of[(R)-[(3aR,4R,6S,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)methoxy]-triethyl-silane(23a) (3.77 g, 6.81 mmol), 1,1-dimethylurea (1.2 g, 13.63 mmol) andK₂CO₃ (2.35 g, 17.04 mmol) in 1,4-Dioxane (30 mL) was added Pd₂(dba)₃(249.62 mg, 0.17 mmol) and xantphos (591.48 mg, 1.02 mmol) under N₂, thereaction mixture was heated to 80° C. and stirred for 18 h. LCMS showedthe reaction was completed, the reaction mixture was filtered throughcelite, and the filtrate was concentrated under reduced pressure to givecrude product, which was purified by silica gel column chromatography(PE:EA=2:1) to give3-[7-[(3aR,4R,6S,6aR)-6-[(R)-4-bicyclo[4.2.0]octa-1,3,5-trienyl(triethylsilyloxy)methyl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidin-4-yl]-1,1-dimethyl-urea(23b) (3.2 g, 4.3 mmol, 63% yield) as a solid.

c) Synthesis of3-[7-[(2R,3R,4S,5R)-5-[(R)-4-bicyclo[4.2.0]octa-1,3,5-trienyl(hydroxy)methyl]-3,4-dihydroxy-tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-4-yl]-1,1-dimethyl-urea(Ex. 23)

To a solution of3-[7-[(3aR,4R,6S,6aR)-6-[(R)-4-bicyclo[4.2.0]octa-1,3,5-trienyl(triethylsilyloxy)methyl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidin-4-yl]-1,1-dimethyl-urea(23b) (1.6 g, 2.16 mmol) in Water (12 mL) and TFA (8.0 mL, 107.7 mmol)was stirred at 25° C. for 1.5 h. LCMS showed the reaction was completed.The solvent was concentrated under reduced pressure, the residue wasdissolved in DMSO and purified by prep-HPLC (0.1% NH₃·H₂O) eluting withH₂O:CH₃CN from 90:10 to 5:95 to give3-[7-[(2R,3R,4S,5R)-5-[(R)-4-bicyclo[4.2.0]octa-1,3,5-trienyl(hydroxy)methyl]-3,4-dihydroxy-tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-4-yl]-1,1-dimethyl-urea(Ex. 23) (600 mg, 1.3503 mmol, 62.64% yield) as a white solid. ¹H NMR(400 MHz, DMSO-d6) δ0 9.45 (s, 1 H), 8.39 (s, 1 H), 7.53 (d, J=3.6 Hz, 1H), 7.21 (d, J=8.0 Hz, 1 H), 7.10 (s, 1H), 7.00 (d, J=7.2 Hz, 1 H), 6.57(d, J=3.2 Hz, 1H), 6.10 (d, J=7.6 Hz, 1 H), 6.00 (s, 1 H), 5.22 (d,J=7.2 Hz, 1 H), 5.01 (d, J=3.6 Hz, 1 H), 4.72 (t, J=4.0 Hz, 1 H),4.53-4.56 (m, 1 H), 4.09 (t, J=4.4 Hz, 1 H), 3.99 (d, J=4.4 Hz, 1H),3.09 (s, 4H), 2.99 (s, 6H). ¹H NMR (400 MHz, DMSO-d6+D₂O ) δ 8.39 (s, 1H), 7.50 (d, J=3.6 Hz, 1 H), 7.21 (d, J=7.6 Hz, 1 H), 7.10 (s, 1 H),7.02 (d, J=7.2 Hz, 1 H), 6.60 (d, J=4.0 Hz, 1 H), 6.09 (d, J=7.6 Hz, 1H), 4.73 (d, J=4.8 Hz, 1 H), 4.55-4.58 (m, 1 H), 4.12 (d, J=5.6 Hz, 1H), 4.03-4.04 (m, 1H), 3.10 (s, 4 H), 3.00 (s, 6 H).

Example 40(2R,3S,4R,5R)-2-[(R)-4-bicyclo[4.2.0]octa-1,3,5-trienyl(hydroxy)methyl]-5-(4-isopropenylpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol(Ex. 40)

a) Synthesis of(R)-[(3aR,4R,6R,6aR)-4-(4-isopropenylpyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl](4-bicyclo[4.2.0]octa-1,3,5-trienyl)methanol(40a)

A mixture of1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (95.43 mg, 0.12 mmol), Potassium carbonate(403.76 mg, 2.92 mmol),(R)-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxo-6-yl]-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)methanol(2a) (500.0 mg, 1.17 mmol), 1,4-Dioxane (30 mL) and Water (6 mL) weredegassed with N₂, was added. The mixture was stirred at 90° C. for 16hrs. LCMS showed the desired mass was detected. The mixture was filteredand concentrated, the residue was purified by combi-flash eluting withCH₃CN/H₂O (neutral) from 5/95 to 95/5 to give(R)-[(3aR,4R,6R,6aR)-4-(4-isopropenylpyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)methanol(40a) (440 mg, 1.02 mmol, 86.9% yield) as a yellow solid.

b)(2R,3S,4R,5R)-2-[(R)-4-bicyclo[4.2.0]octa-1,3,5-trienyl(hydroxy)methyl]-5-(4-isopropenylpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol(Ex. 40)

To a solution of(R)-[(3aR,4R,6R,6aR)-4-(4-isopropenylpyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)methanol(90.0 mg, 0.21 mmol) in CH₃CN (2 mL), TFA (0.8 mL, 11.6 mmol) and water(1.2 mL, 66.59 mmol) were added. The mixture was stirred at 40° C. for 1h. LCMS showed the reaction has been completed. The mixture was purifiedby prep-HPLC eluting with CH₃CN/H₂O (0.1% TFA) from 5/95 to 95/5 to give(2R,3S,4R,5R)-2-[(R)-4-bicyclo[4.2.0]octa-1,3,5-trienyl(hydroxy)methyl]-5-(4-isopropenylpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol(Ex. 40) (44.5 mg, 0.1116 mmol, 53.755% yield) as a white solid. ¹H NMR(400 MHz, DMSO6): δ 8.82 (s, 1 H), 7.92 (d, J=3.6 Hz, 1 H), 7.22 (d,J=8.0 Hz, 1 H), 7.11 (s, 1H), 7.00 (d, J=7.6 Hz, 1H), 6.93 (d, J=3.6 Hz,1 H), 6.23 (d, J=7.6 Hz, 1 H), 6.04 (s, 1 H), 5.74 (s, 1 H), 4.75 (d,J=4.4 Hz, 1 H), 4.56-4.60 (m, 1 H), 4.14 (d, J=4.8 Hz, 1 H), 4.03 (d,J=4.4 Hz, 1 H), 3.09 (s, 4H), 2.28 (s, 3 H). ¹H NMR (400 MHz,DMSO6+D₂O): δ 8.84 (s, 1 H), 7.91 (d, J=3.6 Hz, 1 H), 7.17 (d, J=7.2 Hz,1 H), 7.07 (s, 1 H), 6.97-7.01 (m, 2 H), 6.21 (d, J=7.6 Hz, 1 H), 6.03(s, 1 H), 5.82 (s, 1 H), 4.71 (d, J=4.8 Hz, 1 H), 4.53-4.56 (m, 1 H),4.14 (d, J=5.2 Hz, 1 H), 4.05 (d, J=4.8 Hz, 1 H), 3.06 (s, 4 H), 2.28(s, 3H)

Example 41(2R,3S,4R,5R)-2-[(R)-4-bicyclo[4.2.0]octa-1,3,5-trienyl(hydroxy)methyl]-5-(4-isopropylpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol(Ex. 41)

a) Synthesis of(R)-[(3aR,4R,6R,6aR)-4-(4-isopropylpyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl](4-bicyclo[4.2.0]octa-1,3,5-trienyl)methanol(41a)

To a solution of(R)-[(3aR,4R,6R,6aR)-4-(4-isopropenylpyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)methanol(40a) (340.0 mg, 0.78 mmol) in Methanol (50 mL), Pd/C (340.0 mg, 0.32mmol) was added. The mixture was stirred at 25° C. under a H₂ balloonfor 16 h. LCMS showed the reaction has been completed. The mixture wasfiltered through a pad of celite, the filtrate was concentrated to givethe crude(R)-[(3aR,4R,6R,6aR)-4-(4-isopropylpyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)methanol(41a) (340 mg, 0.781 mmol, 99.5% yield) which was used directly for thenext step.

b)(2R,3S,4R,5R)-2-[(R)-4-bicyclo[4.2.0]octa-1,3,5-trienyl(hydroxy)methyl]-5-(4-isopropylpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol(Ex. 41)

To a solution of(R)-[(3aR,4R,6R,6aR)-4-(4-isopropylpyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)methanol(41a) (340.0 mg, 0.78 mmol) in CH₃CN (3 mL), TFA (1.2 mL, 17 mmol) andwater 1.8 mL) were added. The mixture was stirred at 40° C. for 1 h.LCMS showed the reaction has been completed. The mixture was purified byprep-HPLC eluting with CH₃CN/H₂O (0.1% TFA) from 5/95 to 95/5 to give(2R,3S,4R,5R)-2-[(R)-4-bicyclo[4.2.0]octa-1,3,5-trienyl(hydroxy)methyl]-5-(4-isopropylpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol(Ex. 41) (167.2 mg, 0.416 mmol, 53.3% yield) as a white solid. ¹H NMRverified the product. ¹H NMR (400 M Hz, DMSO6): δ0 8.87 (s, 1 H), 7.94(d, J=3.6 Hz, 1 H), 7.22 (d, J=7.6 Hz, 1 H), 7.12 (s, 1 H), 6.99-7.02(m, 2 H), 6.21 (d, J=7.6 hz, 1 H), 4.75 (d, J=4.8 Hz, 1 H), 4.56-4.60(m, 1H), 4.14 (d, J=4.8 Hz, 1 H), 4.03 (d, J=4.8 Hz, 1 H), 3.49-3.56 (m,1 H), 3.09 (s, 4 H), 1.38 (d, J=6.8 Hz, 6 H). ¹H NMR (400 M Hz,DMSO6+D₂O): δ 8.96 (s, 1 H), 8.03 (d, J=3.6 Hz, 1 H), 7.22 (d, J=3.6 Hz,1 H), 7.17 (d, J=4.0 Hz, 1 H), 7.11 (s, 1 H), 7.02 (d, J=7.6 Hz, 1 H),6.25 (d, J=7.6 Hz, 1 H), 4.75 (d, J=4.8 Hz, 1 H), 4.56-4.59 (m, 1 H),4.17 (d, J=4.8 Hz, 1 H), 4.08 (d, J=4.8 Hz, 1 H), 3.56-3.63 (m, 1 H),3.10 (s, 4 H), 1.43 (d, J=7.2 Hz, 6H).

Example 43(2R,3S,4R,5R)-2-[(R)bicyclo[4.2.0]octa-1,3,5-trienyl(hydroxy)methyl]-5-[4-(hydroxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]tetrahydrofuran-3,4-diol(Ex. 43)

a) Synthesis of methyl7-[(3aR,4R,6R,6aR)-6-[(R)-benzoyloxy(4-bicyclo[4.2.0]octa-1,3,5-trienyl)methyl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine-4-carboxylate(43b)

To a solution of[(R)-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)methyl]benzoate(43a, prepared by procedures similar to that of 11a) (1.0 g, 1.88 mmol)in Methanol (250 mL) was added Pd(dppf)₂Cl₂ (153.51 mg, 0.19 mmol) underCO (5000 mg, 188 mmol), the reaction mixture was stirred at 50° C. for18 h. LCMS showed the starting material was consumed and the desiredproduct was the main peak. The reaction mixture was combined withprevious reactions and purified. The solvent was removed in vacuo. Thereaction mixture was diluted with H₂O (100 mL) and the mixture wasextracted with EA (150 mL & times; 3), then the organic layer was washedwith saturated NaCl (100 mL). The resulting organic layer was dried overanhydrous Na₂SO₄ and the solvent was removed in vacuo. The crude productwas purified by column chromatography on silica gel (100-200 mesh size)using petroleum ether/EtOAc (50:1-1:1) as eluent to give methyl7-[(3aR,4R,6R,6aR)-6-[(R)-benzoyloxy)4-bicyclo[4.2.0]octa-1,3,5-trienyl)methyl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine-4-carboxylate(900 mg, 1.52 mmol, 80.7% yield) as a yellow oil. LCMS [M+H]: 556.2.

b) Synthesis[(R)-[(3aR,4R,6R,6aR)-4-[4-(hydroxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)methyl]benzoate(43c)

To a solution of methyl7-[(3aR,4R,6R,6aR)-6-[(R)-benzoyloxy(4-bicyclo[4.2.0]octa-1,3,5-trienyl)methyl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine-4-carboxylate(43b) (200.0 mg, 0.36 mmol) in THF (20 mL) was added under N₂LiAlH₄(20.49 mg, 0.54 mmol), the reaction mixture was stirred at 0° C. for 2h. LCMS showed the starting material was consumed and the desiredproduct was the main peak. The reaction mixture was combined withprevious reactions and purified. The reaction was quenched with NH₄Cl(aq. 20.0 mL) and water (20.0 mL). The aqueous layer was extracted withEA (200.0 mL×3). The organic layers were concentrated in vacuum. Thecrude product was purified by column chromatography on silica gel(100-200 mesh size) using petroleum ether/EtOAc (50:1-10:1) as eluent togive[(R)-[(3aR,4R,6R,6aR)-4-[r-(hydroxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro-[3,4-d][1,3]dioxol-6-yl]-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)methyl]benzoate(43c) (100 mg, 0.190 mmol, 52.7% yield) as a pale yellow solid.

c) Synthesis of(R)-[(3aR,4R,6R,6aR)-4-[4-(hydroxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)methanol(43d)

A solution of[(R)-[(3aR,4R,6R,6aR)-4-[4-(hydroxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)methyl]benzoate(43c) (70.0 mg, 0.13 mmol) in Ethanol (3.5 mL) and Hydrazinium hydroxide(3.0 mL, 0.13 mmol) was stirred at 25° C. for 1 h. LCMS showed thestarting material was consumed and the desired product was the mainpeak. The residue was purified by flash column chromatography (Eluent of10-90% H₂O/CH₃CH on C˜). Then the resulting product was concentrated invacuum to give(R)-[(3aR,4R,6R,6aR)-4-[4-(hydroxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)methanol(43b) (35 mg, 0.083 mmol, 62% yield) as a pale yellow solid.

d) Synthesis of(2R,3S,4R,5R)-2-[(R)-4-bicyclo[4.2.0]octa-1,3,5-trienyl(hydroxy)methyl]-5-[4-(hydroxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]tetrahydrofuran-3,4-diol(Ex. 43)

A solution of(R)-[(3aR,4R,6R,6aR)-4-[4-(hydroxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)methanol(43d) (35.0 mg, 0.08 mmol) in Water (2 mL) and TFA (2.0 mL, 22.21 mmol)was stirred at 25° C. for 2 hrs. LCMS showed the starting material wasconsumed and the desired product was the main peak. The solvent wasremoved in vacuo and the crude product was purified by prep-HPLC(eluting with H₂O:CH₃CN (1% NH₃·H₂O) form 90:10 to 5:95) to obtain(2R,3S,4R,5R)-2-[(R)-4-bicyclo[4.2.0]octa-1,3,5-trienyl(hydroxy)methyl]-5-[4-(hydroxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]tetrahydrofuran-3,4-diol(Ex. 43) (18.34 mg, 0.0460 mmol, 55.6% yield) as a white solid. LCMS[M+H]: 384.2. ¹H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1 H), 7.76-7.77 (d,J=3.6 Hz, 1 H), 7.20-7.22 (m, 1H), 7.11 (s, 1 H), 6.99-7.01 (s, 1 H),6.89-6.90 (d, J=3.6 Hz, 1 H), 6.17-6.19 (d, J=7.6 Hz, 1 H), 5.90-5.91(d, J=4.0 Hz, 1 H), 5.58-5.61 (m, 1 H), 5.22-5.24 (d, J=7.2 Hz, 1 H),5.04-5.05 (d, J=4.0 Hz, 1 H), 4.82-4.83 (d, J=6.0 Hz, 2 H), 4.73-4.75(m, 1 H), 4.57-4.58 (m, 1 H), 4.11-4.13 (m, 1 H), 4.01-4.02 (m, 1 H),3.09 (s, 4 H). ¹H NMR (400 MHz, DMSO-d6+D₂O) 67 8.69 (s, 1 H), 7.74-7.75(d, J=4.0 Hz, 1 H), 7.20-7.22 (m, 1 H), 7.10 (s, 1 H), 7.00-7.02 (s, 1H), 6.89-6.99 (d, J=3.6 Hz, 1 H), 6.17-6.19 (d, J=7.6 Hz, 1 H), 4.83 (s,2 H), 4.73-4.74 (m, 1 H), 4.56-4.59 (m, 1 H), 4.12-4.13 (m, 1 H),4.02-4.03 (m, 1 H), 3.09 (s, 4H).

Example 48(2R,3S,4R,5R)-2-[(R)-4-bicyclo[4.2.0]octa-1,3,5-trienyl(hydroxy)methyl]-5-[4-(2-methoxyethyl)pyrrolo[2,3-d]pyrimidin-7-yl]tetrahydrofuran-3,4-diol(Ex. 48)

To a solution of[(R)-[(3aR,4R,6S,6aR)-2,2-dimethyl-4-(4-vinylpyrrolo[2,3-d]pyrimidin-7-yl)-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)methoxy]-triethyl-silane(prepared similarly to that of 40a) (50.0 mg, 0.09 mmol) in Methanol (3mL) was added Potassium bisulfate (63.78 mg, 0.47 mmol), the mixture wasstirred at 80° C. 4 hours. LC-MS showed the reaction was completed. Thereaction mixture was filtered, the filtrate was purified by prep-HPLC,eluted with CH₃CN in H₂O (0.1% NH₄OH) from 5.0% to 95.0% to give(2R,3S,4R,5R)-2-[(R)-4-bicyclo[4.2.0]octa-1,3,5-trienyl(hydroxy)methyl]-5-[4-(2-methoxyethyl)pyrrolo[2,3-d]pyrimidin-7-yl]tetrahydrofuran-3,4-diol(Ex. 48) (10 mg, 0.024 mmol, 26% yield) as a white solid. ¹H NMR (400MHz, DMSO-d6+D2O) δ 8.69 (s, 1H), 7.75-7.76 (m, 1H), 7.20-7.22 (m, 1H),7.10 (s, 1H), 7.00-7.01 (m, 1H), 6.81-6.82 (m, 1H), 6.15-6.17 (m, 1H),4.72-4.74 (m, 1H), 4.56-4.60 (m, 1H), 4.11-4.12 (m, 1H), 4.01-4.03 (m,1H), 3.80-3.83 (m, 2H), 3.20-3.24 (m, 5H), 3.06-3.10 (m, 4H).

Example 49(2R,3S,4R,5R)-2-[(R)-4-bicyclo[4.2.0]octa-1,3,5-trienyl(hydroxy)methyl]-5-[4-(fluoromethyl)pyrrolo[2,3-d]pyrimidin-7-yl]tetrahydrofuran-3,4-diol(Ex. 49)

a) Synthesis of[(R)-[(3aR,4R,6S,6aR)-4-[4-(fluoromethyl)pyrrolo[2,3-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)methoxy]-triethyl-silane(49b)

To a solution ofN′-[1-[(3aR,4R,6S,6aR)-6-[(R)-4-bicyclo[4.2.0]octa-1,3,5-trienyl(triethylsilyloxy)methyl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-3-(2-hydroxyethyl)pyrrol-2-yl]-N-methylene-formamidine(49a) (150.0 mg, 0.27 mmol) in DCM (20 mL) was added under DAST (218 mg,1.35 mmol), the reaction mixture was stirred at 25°0 C. for 2 h. LCMSshowed the reaction was completed. The reaction was combined withanother batch and added to water (10 ml), extracted with DCM (20 ml*2).All of the DCM was concentrated and the residue was purified by gelchromatography (SiO2 200-300 mesh, PE:EA=10:1 to 3:1) to give[(R)-[(3aR,4R,6S,6aR)-4-[4-(fluoromethyl)pyrrolo[2,3-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-(4-bicyclo[4.2.0]octa-1,3,5-trienyl)methoxy]-triethyl-silane(49b) (55 mg, 0.096 mmol, 35% yield) as a yellow oil; LCMS M+H⁺540.3.

b) Synthesis of(2R,3S,4R,5R)-2-[(R)-4-bicyclo[4.2.0]octa-1,3,5-trienyl(hydroxy)methyl]-5-[4-(fluoromethyl)pyrrolo[2,3-d]pyrimidin-7-yl]tetrahydrofuran-3,4-diol(Ex. 49)

To a solution of TFA (1.0 mL, 13.46 mmol) and Water (1.5 mL) was addedN′-[1-[(3aR,4R,6S,6aR)-6-[(R)-4-bicyclo[4.2.0]octa-1,3,5-trienyl(triethylsilyloxy)methyl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-3-(2-fluoroethyl)pyrrol-2-yl]-N-methylene-formamidine(55.0 mg, 0.10 mmol), the reaction mixture was stirred at 40° C. for 1h. LCMS showed the reaction was completed. The mixture was concentratedand purified by prep-HPLC eluting with CH₃CN/H₂O (0.1 % TFA) from 5/95to 95/5 to give the prepared solution which as lyophilized to give(2R,3S,4R,5R)-2-[(R)-4-bicyclo[4.2.0]octa-1,3,5-trienyl(hydroxy)methyl]-5-[4-(fluoromethyl)pyrrolo[2,3-d]pyrimidin-7-yl]tetrahydrofuran-3,4-diol(Ex. 49) (21.7 mg, 0.0557 mmol, 56.3% yield) as a white solid. ¹H NMR(DMSO-d6, 400 MHz) δ 8.82 (s, 1H), 7.92 (s, 1H), 7.21 (d, J=8.0 Hz, 1H),7.10 (s, 1H), 7.00 (d, J=7.2 Hz, 1H), 6.84 (s, 1H), 6.23 (d, J=8.0 Hz,1H), 5.87 (s, 1H), 5.76 (s, 1H), 4.74-4.75 (m, 1H), 4.56-4.59 (m, 1H),4.13-4.14 (m, 1H), 4.01-4.03 (m, 1H), 3.08 (s, 4H). ¹H NMR (DMSO-d6D₂O,400 MHz) δ 8.84 (s, 1H), 7.92 (s, 1H), 7.21 (d, J=7.6 Hz, 1H), 7.10 (s,1H), 7.00 (d, J=7.2 Hz, 1H), 6.85 (s, 1H), 6.23 (d, J=7.6 Hz, 1H), 5.80(d, J=44 Hz, 2H), 4.73-4.75 (m, 1H), 4.56-4.59 (m, 1H), 4.13-4.14 (m,1H), 4.02-4.04 (m, 1H), 3.08 (s, 4H).

Example 50 and 51(2R,3R,4S,5R)-2-[4-(ethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]-5-[rac-(R)-3-bicyclo[4.2.0]octa-1,3,5-trienyl(hydroxy)methyl]tetrahydrofuran-3,4-diol(Ex. 50)(2R,3R,4S,5R)-2-[4-(chloromethyl)pyrrolo[2,3-d]pyrimidin-7-yl]-5-[rac-(R)-3-bicyclo[4.2.0]octa-1,3,5-trienyl(hydroxy)methyl]tetrahydrofuran-3,4-diol(Ex. 51)

a) Synthesis oftriethyl-[(R)-3-bicyclo[4.2.0]octa-1,3,5-trienyl-[(3aR,4R,6S,6aR)-4-[4-(chloromethyl)pyrrolo[2,3-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methoxy]silane(50a)

To a solution ofN′-[1-[(3aR,4R,6S,6aR)-6-[(R)-4-bicyclo[4.2.0]octa-1,3,5-trienyl(triethylsilyloxy)methyl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-3-(2-hydroxyethyl)pyrrol-2-yl]N-methylene-formamidine(49a) (100.0 mg, 0.18 mmol) in DCM (10 mL) was added. TsCl (68.86 mg,0.36 mmol), DMPA (4.41 mg, 0.04 mmol) and Triethylamine (0.08 mL, 0.54mmol). The reaction mixture was stirred at 25° C. for 2 h. LCMS showedthe reaction was completed but no tosylate was formed. The mixture wasconcentrated, the residue was purified by pre-TLC (PE:EA=2:1) to givetriethyl-[(R)-3-bicyclo[4.2.0]octa-1,3,5-trienyl-[(3aR,4R,6S,6aR)-4-[4-(chloromethyl)pyrrolo[2,3-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methoxy]silane(50a) (30 mg, 0.05394 mmol, 29.871% yield) as a yellow oil. LCMSM+H⁺556.3/558.3.

b) Synthesis oftriethyl-[rac-(R)-3-bicyclo[4.2.0]octa-1,3,5-trienyl-[rac-(3aR,4R,6S,6aR)-4-[4-(ethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methoxy]silane(50b)

To 50% Ethanol (10 mL) was added Na (2.49 mg, 0.11 mmol), until Na wasdissolved. The solution was added totriethyl-[(R)-3-bicyclo[4.2.0]octa-1,3,5-trienyl-[(3aR,4R,6S,6aR)-4-[4-(chloromethyl)pyrrolo[2,3-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methoxy]silane(30.0 mg, 0.05 mmol) in 50% Ethanol (10 mL) under 0° C. The mixture wasstirred at 25° C. for 1 h. The mixture was added to a mixture of water(20 ml) and EA (20 ml). Extracted with EA (15 ml*2), washed brine (5ml), dried by Na₂SO₄, concentrated to givetriethyl-[rac-(R)-3-bicyclo[4.2.0]octa-1,3,5-trienyl-[rac-(3aR,4R,6S,6aR)-4-[4-(ethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methoxy]silane(30 mg, 0.053 mmol, 98% yield) together with unreacted 50a as a yellowoil.

c) Synthesis of(2R,3R,4S,5R)-2-[4-ethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]-5-[rac-(R)-3-bicyclo[4.2.0]octa-1,3,5-trienyl(hydroxy)methyl]tetrahydrofuran-3,4-diol(Ex. 50)(2R,3R,4S,5R)-2-[4-(chloromethyl)pyrrolo[2,3-d]pyrimidin-7-yl]-5-[rac-(R)-3-bicyclo[4.2.0]octa-1,3,5-trienyl(hydroxy)methyl]tetrahydrofuran-3,4-diol(Ex. 51)

To a solution of TFA (1.0 mL, 13.46 mmol) and Water (1.5 mL) was amixture of 50a and 50b (30.0 mg, 0.05 mg), the reaction mixture wasstirred at 40° C. for 1 h. LCMS showed the reaction was completed. Themixture was concentrated and purified by prep-HPLC eluting withCH₃CN/H₂O (0.1% NH₃OH) from 5/95 to 95/5 to give the prepared solutionwhich was lyophilized to give(2R,3R,4S,5R)-2-[4-(ethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]-5-[rac-(R)-3-bicyclo[4.2.0]octa-1,3,5-trienyl(hydroxy)methyl]tetrahydrofuran-3,4-diol(Ex. 50) (2 mg, 0.0048 mmol, 8.9% yield) as a white solid and(2R,3R,4S,5R)-2-[4-(chloromethyl)pyrrolo[2,3-d]pyrimidin-7-yl]-5-[rac-(R)-3-bicyclo[4.2.0]octa-1,3,5-trienyl(hydroxy)methyl]tetrahydrofuran-3,4-diol(10.1 mg, 0.024 mmol, 45% yield) as a yellow solid.

-   Ex. 50. ¹H NMR (DMSO-d6, 400 MHz) δ 8.75 (s, 1H), 7.94 (s, 1H), 7.21    (d, J=7.6 Hz, 1H), 7.10 (s, 1H), 7.00 (d, J=7.6 hz, 1H), 6.85 (s,    1H), 6.20 (d, J=8.0 Hz, 1H), 4.83 (s, 2 H), 4.73-4.74 (m, 1H),    4.56-4.59 (m, 1H), 4.12-4.13 (m, 1H), 4.01-4.02 (m, 1H), 3.56-3.61    (m, 2H), 3.08 (s, 4H), 1.19-1.23 (m, 3H); (DMSO-d6+D2O), 400 MHz) δ    8.77 (s, 1H), 7.85 (s, 1H), 7.21 (d, J=7.6 Hz, 1H), -7.10 (s, 1H),    7.00 (d, J=7.6 Hz, 1H), 6.87 (2, 1H), 6.20 (d, J=7.6 Hz, 1H), 4.85    (s, 2 H), 4.73-4.74 (m, 1H), 4.56-4.59 (m, 1H), 4.12-4.13 (m, 1H),    4.02-4.03 (m, 1H), 3.57-3.62 (m, 2H), 3.09 (s, 4H), 1.20-1.23 (m,    3H).-   Ex. 51 ¹H NMR (DMSO-d6, 400 MHz) δ 8.80 (s, 1H), 7.92 (s, 1H), 7.21    (d, J=7.6 Hz, 1H), 7.10 (s, 1H), 7.00 (d, J=7.6 Hz, 1H), 6.93 (s,    1H), 6.20 (d, J=8.0 Hz, 1H), 5.01-5.05 (m, 2 H), 4.73-4.75 (m, 1H),    4.56-4.59 (m, 1H), 4.12-4.14 (m, 1H), 4.01-4.02 (m, 1H), 3.08 (s,    4H); ¹H NMR (DMSO-d6+D2O, 400 MHz) δ 8.80 (s, 1H), 7.92 (s, 1H),    7.21 (d, J=7.6 Hz, 1H), 7.10 (s, 1H), 7.00 (d, J=7.6 Hz, 1H), 6.93    (s, 1H), 6.20 (d, J=8.0 Hz, 1H), 5.01-5.05 (m, 2H), 4.73-4.74 (m,    1H), 4.56-4.59 (m, 1H), 4.12-4.14 (m, 1H), 4.02-4.03 (m, 1H), 3.08    (s, 4H).

TABLE 1 Examples prepared using procedures analogous to those describedabove. Prepared as Ex. # Structure in Ex. # Spectral data 9

11 ¹H NMR (400 MHz, DMSO-d₆) δ 8.67 (s, 1H), 7.84 (d, J = 3.7 Hz, 1H),7.39 (d, J = 7.8 Hz, 1H), 7.26 (s, 1H), 7.05 (d, J = 7.8 Hz, 1H), 6.79(d, J = 3.7 Hz, 1H), 6.09 (d, J = 8.1 Hz, 1H), 6.04 (s, 1H), 5.17 (d, J= 7.1 Hz, 1H), 4.80 (d, J = 3.6 Hz, 1H), 4.56 (dd, J = 7.7, 12.7 Hz,1H), 4.11 (s, 1H), 3.73 (t, J = 4.4 Hz, 1H), 3.12 (s, 4H), 2.68 (s, 3H),1.40 (s, 3H). 14

1, 2 LCMS [M + H]: 385.1. ¹H NMR (600 Hz, DMSO- d6) δ 8.05 (s, 1H), 7.32(d, J = 3.6 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 7.08 (s, 2H), 6.86 (d, J= 7.5 Hz, 1H), 6.79 (s, 1H), 6.59 (d, J = 3.6 Hz, 1H), 6.52 (d, J = 3.4Hz, 1H), 5.89 (d, J = 7.9 Hz, 1H), 5.15 (d, J = 7.1 Hz, 1H), 4.92 (d, J= 3.8 Hz, 1H), 4.73 (t, J = 3.5 Hz, 1H), 4.62 (td, J = 5.0, 7.5 Hz, 1H),4.50 (t, J = 8.7 Hz, 2H), 4.02 (t, J = 4.4 Hz, 1H), 4.00 (dd, J = 1.0,4.0 Hz, 1H), 3.13 (t, J = 8.6 Hz, 2H). ¹H NMR (600 MHz, DMSO-d6 + D₂O) δ8.03 (s, 1H), 7.29 (d, J = 3.7 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 6.84(d, J = 7.5 Hz, 1H), 6.75 (s, 1H), 6.58 (d, J = 3.6 Hz, 1H), 5.87 (d, J= 7.9 Hz, 1H), 4.70 (d, J = 4.0 Hz, 1H), 4.59 (dd, J = 5.0, 7.9 Hz, 1H),4.47 (t, J = 8.7 Hz, 2H), 4.02 (dd, J = 1.1, 5.1 Hz, 1H), 3.99 (dd, J =0.7, 4.1 Hz, 1H), 3.11 (t, J = 8.7 Hz, 2H). 35

2 ¹H NMR (400 MHz, Methanol-d4) δ 8.39 (s, 1H), 7.39 (d, J = 3.6 Hz,1H), 7.28 (d, J = 7.6 Hz, 1H), 7.16 (s, 1H), 7.02 (d, J = 7.6 Hz, 1H),6.57 (d, J = 3.6 Hz, 1H), 6.02 (d, J = 7.5 Hz, 1H), 4.96 (d, J = 2.1 Hz,2H), 4.78 (dd, J = 5.1, 7.4 Hz, 1H), 4.26 (m, 2H), 4.12 (s, 3H), 3.16(s, 4H). 36

6 LCMS [M + H]: 447.1/449.1. ¹H NMR (400 MHz, DMSO-d6): δ 8.10 (s, 1 H),7.52 (s, 1 H), 7.21 (d, J = 7.6 Hz, 1 H), 7.11 (s, 1 H), 7.01 (d, J =7.6 Hz, 1 H), 6.83 (brs, 2 H), 6.07 (d, J = 3.6 Hz, 1 H), 5.99 (d, J =7.6 Hz, 1 H), 5.24 (d, J = 6.4 Hz, 1 H), 4.99 (d, J = 3.6 Hz, 1 H),4.72-4.75 (m, 1 H), 4.44- 4.49 (m, 1 H), 4.02-4.04 (m, 1 H), 4.00 (d, J= 4.0 Hz, 1 H), 3.10 (s, 4 H). ¹H NMR (400 MHz, DMSO-d6 + D₂O): δ 8.11(s, 1 H), 7.41 (s, 1 H), 7.20 (d, J = 7.6 Hz, 1 H), 7.10 (s, 1 H), 7.03(d, J = 7.6 Hz, 1 H), 5.99 (d, J = 7.6 Hz, 1 H), 4.74 (d, J = 4.0 Hz, 1H), 4.43-4.46 (m, 1 H), 4.04-4.07 (m, 2 H), 3.11 (s, 4 H). 37

6 LCMS [M + H]: 495.0. ¹H NMR (400 MHz, DMSO- d6): δ 8.10 (s, 1 H), 7.51(s, 1 H), 7.21 (d, J = 7.2 Hz, 1 H), 7.11 (s, 1 H), 7.02 (d, J = 7.6 Hz,1 H), 6.70 (brs, 2 H), 6.09 (d, J = 4.0 Hz, 1 H), 5.97 (d, J = 7.6 Hz, 1H), 5.23 (d, J = 6.8 Hz, 1 H), 4.99 (d, J = 4.0 Hz, 1 H), 4.73-4.75 (m,1 H), 4.43-4.48 (m, 1 H), 4.00-4.03 (m, 2H), 3.11 (s, 4H). ¹H NMR (400MHz, DMSO-d6 + D₂O): δ 8.11 (s, 1 H), 7.44 (s, 1 H), 7.20 (d, J = 7.6Hz, 1 H), 7.10 (s, 1 H), 7.03 (d, J = 7.6 Hz, 1 H), 5.97 (d, J = 7.6 Hz,1 H), 4.74 (d, J = 3.6 Hz, 1 H), 4.42-4.45 (m, 1 H), 4.03-4.05 (m, 2 H),3.12 (s, 4 H). 38

6 LCMS [M + H]: 437.3. ¹H NMR (400 MHz, DMSO- d6): δ 8.26 (s, 1 H), 8.10(s, 1 H), 7.22 (d, J = 7.2 Hz, 1 H), 7.11 (s, 1 H), 7.01 (d, J = 7.6 Hz,1H), 6.07 (d, J = 7.6 Hz, 1 H), 4.78 (d, J = 4.0 Hz, 1 H), 4.54-4.58 (m,1 H), 4.07 (d, J = 4.0 Hz, 1 H), 4.03 (d, J = 4.0 Hz, 1 H), 3.09 (s, 4H). ¹H NMR (400 MHz, DMSO-d6 + D₂O): δ 8.31 (s, 1 H), 8.10 (s, 1 H),7.21 (d, J = 7.6 Hz, 1 H), 7.11 (s, 1 H), 7.02 (d, J = 7.6 Hz, 1 H),6.09 (d, J = 7.6 Hz, 1 H), 4.78 (d, J = 3.6 Hz, 1 H), 4.52-4.56 (m, 1H), 4.09 (d, J = 4.8 Hz, 1 H), 4.06 (d, J = 4.0 Hz, 1 H), 3.10 (s, 4 H).¹⁹F NMR (376 MHz, DMSO-d6): δ −53.74 (s, 3 F) 39

1 ¹H NMR (500 MHz, DMSO-d6 + D₂O) δ 8.07 (s, 1H), 7.25 (dd, J = 1.5, 7.8Hz, 1H), 7.14 (d, J = 3.6 Hz, 1H), 7.10 (s, 1H), 6.90 (d, J = 7.8 Hz,1H), 6.51 (d, J = 3.5 Hz, 1H), 5.68 (d, J = 7.8 Hz, 1H), 4.40 (dd, J =5.3, 7.8 Hz, 1H), 4.24-4.18 (m, 2H), 3.01 (s, 4H), 1.38 (s, 3H). 42

11 1H NMR (400 MHz, DMSO-d6): δ 8.72 (s, 1 H), 7.79-7.80 (d, J = 3.6 Hz,1 H), 7.20-7.22 (m, 1 H), 7.10 (s, 1 H), 7.00-7.01 (m, 1 H), 6.82-6.83(d, J = 3.6 Hz, 1 H), 6.15-6.17 (d, J = 8.00 Hz, 1 H), 5.94 (s, 1 H),5.28 (s, 1 H), 5.08 (s, 1 H), 4.73-4.74 (d, J = 4.8 Hz, 1 H),4.57-4.60(m, 1 H), 4.11-4.12 (d, J = 4.8 Hz, 1 H), 4.01-4.02 (d, J = 4.4Hz, 1 H), 3.09 (m, 4 H), 2.98-3.02 (m, 2 H), 1.72-1.78 (m, 2 H), 1.31-1.37 (m, 2 H), 0.89-0.93 (m, 3 H) 1H NMR (400 MHz, DMSO-d6 + D₂O): δ8.71 (s, 1 H), 7.77-7.78 (d, J = 4.0 Hz, 1 H), 7.20-7.22 (m, 1 H), 7.10(s, 1 H), 7.00-7.02 (m, 1 H), 6.83 (d, J = 3.6 Hz, 1 H), 6.15-6.17 (d, J= 7.6 Hz, 1 H), 4.73-4.74 (m, 1 H), 4.57-4.60 (m, 1 H), 4.12-4.13 (d, J= 3.6 Hz, 1 H), 4.02-4.03 (d, J = 4.8 Hz, 1 H), 3.09 (m, 4 H), 2.98-3.02(m, 2 H), 1.72-1.78 (m, 2 H), 1.31- 1.37 (m, 2 H), 0.89-0.93 (m, 3 H) 44

11 LCMS [M + H]: 382.0. ¹H NMR (500 MHz, DMSO- d6) δ 8.69 (s, 1H), 7.79(d, J = 3.5 Hz, 1H), 7.29 (s, 1H), 7.18 (s, 2H), 6.81 (d, J = 3.5 Hz,1H), 6.19 (d, J = 7.8 Hz, 1H), 5.97 (d, J = 3.5 Hz, 1H), 5.26 (d, J =6.8 Hz, 1H), 5.16-5.02 (m, 1H), 4.79 (s, 1H), 4.62 (q, J = 6.8 Hz, 1H),4.15 (s, 1H), 4.07 (d, J = 4.2 Hz, 1H), 2.85 (t, J = 7.2 Hz, 4H), 2.70(s, 3H), 2.03 (p, J = 7.2 Hz, 2H). 45

2 LCMS [M + H]: 383.0. ¹H NMR (500 MHz, DMSO- d6) δ 8.09 (s, 1H),7.39-7.26 (m, 2H), 7.26-7.08 (m, 4H), 6.63 (d, J = 3.5 Hz, 1H), 6.56 (d,J = 2.6 Hz, 1H), 5.94 (d, J = 7.9 Hz, 1H), 5.20 (d, J = 7.1 Hz, 1H),4.96 (d, J = 3.7 Hz, 1H), 4.80 (s, 1H), 4.66 (q, J = 7.4 Hz, 1H),4.15-4.05 (m, 2H), 2.93-2.79 (m, 4H), 2.04 (p, J = 7.3 Hz, 2H). 46

40 1HNMR (DMSO-d6 + D₂O, 400 MHz): δ 8.75 (s, 1H), 7.83-7.84 (m, 1H),7.19-7.26 (m, 2H), 7.10 (s, 1H), 6.96-7.01 (m, 2H), 6.61-6.66 (m, 1H),6.17-6.19 (m,1H), 5.82-5.85 (m, 1H), 4.73-4.74 (m, 1H), 4.57- 4.60 (m,1H), 4.12-4.14 (m, 1H), 4.02-4.04 (m, 1H), 3.06-3.10 (m, 4H) 47

11 LCMS [M + H]: 368.2. ¹H NMR (400 MHz, DMSO- d6) δ 8.92 (s, 1 H),8.11-8.12 (d, J = 3.6 Hz, 1 H), 7.17-7.19 (d, J = 7.2 Hz,1H), 7.07-7.08(d, J = 3.2 Hz, 2 H), 6.98-7.00 (d, J = 7.2 Hz, 1 H), 6.20- 6.21(d, J =6.4 Hz,1H), 4.79-4.80(d, J = 3.2 Hz, 1 H), 4.37-4.40 (m, 1 H), 4.15-4.17(m, 1 H), 44.07-4.08 (m, 1 H), 3.07 (s, 4 H), 2.81 (s, 3 H). ¹H NMR (400MHz, DMSO-d6 + D2O) δ 8.98(s, 1H), 8.21 (s, 1 H), 7.18 (s, 2H), 7.08 (s,1H), 6.99-7.01 (d, J = 7.6 Hz, 1H), 6.23-6.24 (d, J = 6.8 Hz, 1 H),4.71(s, 1H), 4.40-4.43 (m, 1H), 4.20 (s, 1 H), 4.11(s, 1 H), 3.06 (s,4H), 2.87 (s, 3 H). 52

11 LCMS [M + H]: 389.0. ¹H NMR (500 MHz, DMSO- d6) δ 8.65 (s, 1H), 7.66(d, J = 3.7 Hz, 1H), 6.91 (d, J = 4.9 Hz, 1H), 6.77 (d, J = 3.7 Hz, 1H),6.17 (d, J = 7.5 Hz, 1H), 5.29 (d, J = 6.9 Hz, 1H), 5.13 (d, J = 4.3 Hz,1H), 5.03-4.90 (m, 1H), 4.53 (td, J = 5.0, 7.2 Hz, 1H), 4.30 (dd, J =1.5, 3.4 Hz, 1H), 4.15- 4.01 (m, 1H), 2.83 (t, J = 7.2 Hz, 2H), 2.72 (t,J = 6.9 Hz, 2H), 2.65 (s, 3H), 2.41 (p, J = 7.2 Hz, 2H). 53

48 ¹H NMR (400 MHz, DMSO-d6 + D₂O): δ 8.69 (s, 1H), 7.74-7.75 (m, 1H),7.20-7.22 (m, 1H), 7.10 (s, 1H), 7.00-7.01 (m, 1H), 6.78-6.79 (m, 1H),6.14- 6.16 (m, 1H), 4.73-4.74 (m, 1H), 4.56-4.60 (m, 1H), 4.11-4.12 (m,1H), 4.01-4.03 (m, 1H), 3.84-3.88 (m, 2H), 3.12-3.15 (m, 2H), 3.06-3.10(m, 4H) 54

2 LCMS [M + H]: 383.1. ¹H NMR (400 MHz, DMSO- d6 + D₂O) δ 8.14(s,1H),7.30 (d, J = 3.6 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.11(s, 1H),7.03 (d,J = 7.6 Hz, 1H), 6.58 (d, J = 3.6 Hz, 1 H), 5.91 (d, J = 7.6 Hz, 1 H),4.75(d, J = 4.0 Hz, 1H), 4.60-4.63 (m,1H), 4.03-4.06 (m, 2 H), 3.10 (s,4H), 2.96 (s, 3 H). 55

48 ¹H NMR (400 MHz, DMSO-d₆ + D₂O): δ 8.69 (s, 1H), 7.75-7.76 (m, 1H),7.29-7.33 (m, 2H), 7.20- 7.27 (m, 4H), 7.10 (s, 1H), 7.00-7.01 (m, 1H),6.82- 6.83 (m, 1H), 6.15-6.17 (m, 1H), 4.73-4.74 (m, 1H), 4.56-4.60 (m,1H), 4.48 (s, 2H), 4.11-4.12 (m, 1H), 4.01-4.03 (m, 1H), 3.91-3.94 (m,2H), 3.26-3.29 (m, 2H), 3.06-3.10 (m, 4H). 56

2 LCMS [M + H]: 388.3. ¹H NMR (400 MHz, DMSO- d6) δ 8.66 (s, 1 H), 7.98(d, J = 3.6 Hz,1H), 7.20 (d, J = 7.2 Hz, 1H), 7.10 (s, 1 H), 7.00 (d, J= 7.6 Hz, 1H), 6.78 (d, J = 3.6 Hz, 1H), 6.20 (d, J = 7.6 Hz, 1H), 5.82(s, 1 H), 5.31(s, 1 H), 5.10 (s, 1 H), 4.74 (s, 1 H), 4.55-4.58 (m, 1H), 4.14 (d, J = 3.6 Hz, 1H), 4.03 (d, J = 4.4 Hz,1H), 3.08 (s, 4 H). ¹HNMR (400 MHz, DMSO-d6 + D2O) δ 8.66(s, 1H), 7.92 (d, J = 4.0 Hz, 1H),7.20 (d, J = 7.6 Hz, 1H), 7.09(s, 1H), 7.00 (d, J = 7.2 Hz, 1H), 6.78(d, J = 3.6 Hz, 1 H), 6.19 (d, J = 7.2 Hz, 1 H), 4.73(d, J = 4.8 Hz,1H), 4.55-4.59 (m, 1H), 4.16 (d, J = 4.8 Hz, 1 H), 4.05 (d, J = 4.8 Hz,1 H), 3.09 (s, 4 H).

X-Ray Structure Determination of Example 11

Compound of Example 11 was recrystallized from ethanol. Crystalssuitable for X-ray diffraction studies were obtained as clear colorlessprisms. A clear colourless block-like specimen of C₂₀H₂₁N₃O₄,approximate dimensions 0.071 mm×0.081 mm×0.353 mm, was used for theX-ray crystallographic analysis. Table 1 shows crystal data details.

The total exposure time was 20.12 hours. The frames were integrated withthe Bruker SAINT software package using a narrow-frame algorithm. Theintegration of the data using an orthorhombic unit cell yielded a totalof 20159 reflections to a maximum θ angle of 75.42° (0.80 Å resolution),of which 3565 were independent (average redundancy 5.655,completeness=99.8%, R_(int)=5.73%, R_(sig)=5.24%) and 3401 (95.40%) weregreater than 2σ(F²). The final cell constants of a=7.1738(3) Å,b=13.4258(6) Å, c=16.6573(7) Å, volume=1725.10(13) Å³, are based uponthe refine of the XYZ-centroids of 9173 reflections above 20 σ(I) with8.458°<2θ<150.7°. Data were corrected for absorption effects using theMulti-Scan method (SADABS). The ratio of minimum to maximum apparenttransmission was 0.843. The calculated minimum and maximum transmissioncoefficients (based on crystal size) are 0.7600 and 0.9440.

FIG. 1 show an ORTEP representation of the compound of Example 11. Thestructure was solved and refined using the Bruker SHELXTL SoftwarePackage, using the space group P 21 21 21, with Z=4 for the formulaunit, C₂₀H₂₁N₃O₄. The final anisotropic full-matrix least-squaresrefinement on F² with 328 variables converged at RT=3.27%, for theobserved data and wR2=9.03% for all data. The goodness-of-fit was 1.113.The largest peak in the final difference electron density synthesis was0.235 e⁻/Å³ and the largest hole was −0.165 e⁻/Å³ with an RMS deviationof 0.039 e⁻/Å³. On the basis of the final model, the calculated densitywas 1.415 g/cm³ and F(000), 776 e⁻.

TABLE 2 Sample and crystal data for compound of Example 11 Chemicalformula C₂₀H₂₁N₃O₄ Chemical formula C20H21N3O4 Formula weight 367.40g/mol Temperature 200(2) K Wavelength 1.54178 Å Crystal size 0.071 ×0.081 × 0.353 mm Crystal system orthorhombic Space group P 21 21 21 Unitcell dimensions a = 7.7138(3) Å α = 90° b = 13.4258(6) Å β = 90° c =16.6573(7) Å γ = 90° Volume 1725.10(13) Å3 Z 4 Density (calculated)1.415 g/cm3 Absorption coefficient 0.822 mm−1 F(000) 776

Additional information on the crystal structure of compound of Example11 is listed in Tables 3 to 6.

TABLE 3 Data collection and structure refinement for compound of Example11 Theta range for data 4.23 to 75.42° collection Index ranges −9 <= h<= 9, −16 <= k <= 16, −20 <= l <= 20 Reflections collected 20159Independent reflections 3565 [R(int) = 0.0573] Coverage of independent99.8% reflections Absorption correction Multi-Scan Max. and min. 0.9440and 0.7600 transmission Structure solution direct methods techniqueStructure solution SHELXT 2014/5 (Sheldrick, 2014) program Refinementmethod Full-matrix least-squares on F2 Refinement program SHELXL-2017/1(Sheldrick, 2017) Function minimized Σ w(Fo2 − Fc2)2Data/restraints/parameters 3565/0/328 Goodness-of-fit on F2 1.113 FinalR indices 3401 data; I > 2σ(I)R1 = 0.0327, wR2 = 0.0893 all data R1 =0.0341, wR2 = 0.0903 Weighting scheme w = 1/[σ2(Fo2) + (0.0456P)2 +0.1670P] where P = (Fo2 + 2Fc2)/3 Absolute structure −0.02(12) parameterLargest diff. peak and 0.235 and −0.165 eÅ−3 hole R.M.S. deviation from0.039 eÅ−3 mean

TABLE 4 Atomic coordinates and equivalent isotropic atomic displacementparameters (Å²) for compound of Example 11 x/a y/b z/c U(eq) O1 0.35067(19) 0.51192(11) 0.50048(9)  0.0239(3) O2 0.7564(2) 0.56138(12)0.52052(9)  0.0255(3) O3 0.6275(2) 0.69670(10) 0.41234(9)  0.0220(3) O40.0702(2) 0.65445(13) 0.48013(11) 0.0313(4) N1 0.4819(2) 0.36100(13)0.46699(10) 0.0224(4) N2 0.4867(2) 0.39430(12) 0.32441(10) 0.0217(4) N30.4028(2) 0.25394(14) 0.24387(11) 0.0256(4) C1 0.4433(3) 0.27695(16)0.51247(13) 0.0281(5) C2 0.4023(3) 0.19886(16) 0.46548(13) 0.0288(5) C30.4108(3) 0.23408(15) 0.38424(13) 0.0222(4) C4 0.3806(3) 0.19501(15)0.30821(13) 0.0232(4) C5 0.4557(3) 0.34869(16) 0.25531(13) 0.0245(4) C60.4617(3) 0.33532(14) 0.38774(12) 0.0196(4) C7 0.3210(4) 0.09047(18)0.29500(16) 0.0341(5) C8 0.5105(3) 0.45907(15) 0.50091(12) 0.0200(4) C90.6481(3) 0.52374(15) 0.45895(11) 0.0191(4) C10 0.5383(2) 0.60494(14)0.41844(11) 0.0174(4) C11 0.3763(3) 0.61100(14) 0.47102(11) 0.0193(4)C12 0.2135(3) 0.64621(16) 0.42613(13) 0.0223(4) C13 0.1624(3)0.57846(16) 0.35770(12) 0.0217(4) C14 0.0761(2) 0.48835(16) 0.37308(12)0.0227(4) C15 0.0377(3) 0.43064(16) 0.30696(13) 0.0237(4) C16 0.9541(3)0.33320(18) 0.28065(15) 0.0302(5) C17 0.0003(3) 0.36463(18) 0.19238(14)0.0320(5) C18 0.0817(3) 0.45753(18) 0.22887(13) 0.0268(4) C19 0.1695(3)0.54464(19) 0.21257(13) 0.0289(5) C20 0.2071(3) 0.60495(17) 0.27913(13)0.0254(4) U(eq) is defined as one third of the trace of theorthogonalized Uij tensor

TABLE 5 Bond lengths (Å) for compound of Example 11 O1—C8 1.422(2)O1—C11 1.432(2) O2—C9 1.416(2) O2—H1 0.83(4)  O3—C10 1.415(2) O3—H20.83(3)  O4—C12 1.429(2) O4—H3 0.90(3)  N1—C6 1.373(3) N1—C1 1.392(3)N1—C8 1.450(3) N2—C5 1.325(3) N2—C6 1.333(3) N3—C4 1.343(3) N3—C51.350(3) C1—C2 1.346(3) C1—H4 0.99(3)  C2—C3 1.435(3) C2—H5 1.03(3) C3—C4 1.390(3) C3—C6 1.416(3) C4—C7 1.493(3) C5—H6 1.03(3)  C7—H70.96(4)  C7—H8 0.96(4)  C7—H9 0.95(5)  C8—C9 1.539(3) C8—H10 0.96(2) C9—C10 1.537(3) C9—H11 0.99(3)  C10—C11 1.528(3) C10—H12 0.98(2) C11—C12 1.536(3) C11—H13 0.96(3)  C12—C13 1.511(3) C12—H14 1.00(2) C13—C20 1.399(3) C13—C14 1.404(3) C14—C15 1.379(3) C14—H15 0.97(3) C15—C18 1.392(3) C15—C16 1.523(3) C16—C17 1.571(3) C16—H16 0.98(3) C16—H17 0.98(3)  C17—C18 1.523(3) C17—H18 1.01(4)  C17—H19 0.99(3) C18—C19 1.379(3) C19—C20 1.403(3) C19—H20 0.96(3)  C20—H21 0.97(3) 

TABLE 6 Hydrogen atomic coordinates and isotropic atomic displacementparameters (Å2) for compound of Example 11 x/a y/b z/c U(eq) H1 0.831(5)0.597(3) 0.4992(19) 0.047(9) H2 0.628(5) 0.715(2) 0.365(2)  0.039(8) H30.085(4) 0.704(2) 0.5158(17) 0.029(7) H4 0.453(4) 0.280(2) 0.5714(17)0.037(8) H5 0.374(4) 0.127(2) 0.4831(17) 0.037(7) H6 0.471(4) 0.389(2)0.2034(15) 0.026(6) H7 0.307(4) 0.055(3) 0.344(2)  0.049(9) H8 0.404(5)0.054(3) 0.263(2)   0.057(10) H9 0.213(6) 0.087(3) 0.267(3)   0.085(14)H10 0.546(3)  0.4494(17) 0.5555(13) 0.013(5) H11 0.717(4) 0.484(2)0.4205(17) 0.030(7) H12 0.505(3)  0.5811(16) 0.3651(13) 0.009(5) H130.397(4) 0.657(2) 0.5144(15) 0.024(6) H14 0.237(3)  0.7155(18)0.4062(13) 0.015(5) H15 0.049(3) 0.469(2) 0.4275(16) 0.023(6) H160.004(4) 0.272(2) 0.3028(16) 0.028(7) H17 −0.170(5)   0.329(3)0.2927(19) 0.044(9) H18 0.088(5) 0.319(3) 0.1660(19) 0.052(9) H19−0.098(4)   0.376(2) 0.1548(17) 0.039(8) H20 0.203(4) 0.561(2)0.1587(18) 0.031(7) H21 0.269(4) 0.667(2) 0.2701(18) 0.036(7)

Biochemical Assay Protocol

HotSpot Assay. Compounds were solubilized and 3-fold diluted in 100%DMSO. These diluted compounds were further diluted in the assay buffer(50 mM Tris-HCl, pH 8.5, 50 mM NaCl, 5 mM MgCl₂0.01% Brij35, 1 mM DTT,1% DMSO) for 10 dose IC₅₀ mode at a concentration 10-fold greater thanthe desired assay concentration. Standard reactions were performed in atotal volume of 50 μl in assay buffer, with histone H2A (5 μM final) assubstrate. To this was added the PRMT5/MEP50 complex diluted to providea final assay concentration of 5 nM and the compounds were allowed topreincubate for 15 to 20 minutes at room temperature. The reaction wasinitiated by adding S-[3 H-methyl]-adenosyl-L-methionine (PerkinElmer)to final concentration of 1 μM. Following a 60 minutes incubation at 30°C., the reaction was stopped by adding 100 μL of 20% TCA. Each reactionwas spotted onto filter plate (MultiScreen FB Filter Plate, Millipore),and washed 5 times with PBS buffer, Scintillation fluid was added to thefilter plate and read in a scintillation counter. IC₅₀ values weredetermined by fitting the data to the standard 4 parameters with HillSlope using GraphPad Prism software. This procedure generated theHotSpot data in Table 7.

Flash plate assay. Compounds were solubilized, and 3-fold diluted in100% DMSO. These diluted compounds were further diluted in the assaybuffer (20 mM Tris-HCl, pH 8.0, 50 mM NaCl, 0.002% Tween20, 1 mM TCEP,1% DMSO) for 10-dose IC50 mode at a concentration 10-fold greater thanthe desired assay concentration. Standard reactions were performed in atotal volume of 30 μl in assay buffer, with 300 mN histone H4 basedAcH4-23 (Anaspec: AS-650002) as substrate. To this was added thePRMT5/MEP50 complex diluted to provide a final assay concentration of2.5 nM and the compounds were allowed to preincubate for 20 minutes at37° C. The reaction was initiated by addingS-[3H-methyl]-adenosyl-L-methionine (PerkinElmer: NET155001MC) to finalconcentration of 1 μM. Following a 30 minutes incubation at 37° C., thereaction was stopped by adding 25 μL of 8M Guanidine HCl. Preparestreptavidin YSI SPA beads (Perkinelmer: RPNQ0012) at 0.3 mg/mL in assaybuffer. To each reaction, add 150 μL of SPA beads suspension, andincubated while shaking at room temperature for 30 minutes. The platewas centrifuged at 100×g for 30 second before reading in a scintillationcounter. IC50 values were determined by fitting the data to the standard4 parameters with Hill Slope using GraphPad Prism software. Thisprocedure produced the Flash Plate data in Table 7.

Cellular Assay Protocol

Cell Treatment and Western Blotting for Detecting Symmetric Di-MethylArginine (sDMA) and Histone H3R8 Dimethyl Symmetric (H3R8me2s) Marks

Initial compounds screening in A549 cells. Compounds can be dissolved inDMSO to make 10 mM stock and can be further diluted to 0.1, and 1 mM.A549 cells are maintained in PRMI 1640 (Corning Cellgro, Catalog #:10-040-CV) medium supplemented with 10% v/v FBS (GE Healthcare, Catalog#: SH30910.03). One day before experiment, 1.25×10⁵ cells are seeded in6 well plate in 3 mL medium and incubated overnight. The next day,medium is changed and 3 uL of compound solution is added (1:1,000dilution, 0.1 and 1 uM final concentration; DMSO concentration 0.1%),and incubated for 3 days. Cells incubated with DMSO are used as avehicle control. Cells are washed once with PBS, trypsinized in 150 uL,0.25% Trypsin (Corning Catalog #: 25-0053-CI), neutralized with 1 ml,complete medium, transferred to micr°Centrifuge tubes and collected.Cell pellet are then resuspended in 15 uL PBS, lysed in 4% SDS, andhomogenized by passing through homogenizer column (Omega Biotek, Catalog#: HCR003). Total protein concentrations are determined by BCA assay(ThermoFisher Scientific, Catalog #: 23225). Lysates are mixed with 5×Laemmli buffer and boiled for 5 min. Forty ug of total protein isseparated on SDS-PAGE gels (Bio-Rad, catalog #: 4568083, 4568043),transferred to PVDF membrane, bl°Cked with 5% dry milk (Bio-Rad Catalog#: 1706404) in TBS with 0.1% v/v Tween 20 (TBST) for 1 hour at roomtemperature (RT), and incubated with primary antibodies (sDMA: Cellsignaling, Catalog #: 13222, 1:3,000; H3R8me2s: Epigentek, Catalog #:A-3706-100, 1:2,000; β-Actin: Abcam, Catalog #: ab822, 1:10,000) in 5%dry milk in TBST at 4° C. for overnight. The next day, membranes arewashed with TBST, 5×5 min, and incubated with HRP conjugated secondedantibody (GE Healthcare; Catalog #: NA934-1ML; 1:5,000) for 2 hours atRT, followed by 5×5 min washes with TBST, and incubation with ECLsubstrates (Bio-Rad, Catalog #: 1705061, 1705062). Chemiluminescentsignal is captured with Fluochem HD2 imager (Proteinsimple) and analyzedby ImageJ.

To determine enzyme inhibition IC₅₀ values using Western Blot analysis,Granta cells can be seeded at density of 5×10⁵ cells/mL in 3 mL medium(PRMI+10% v/v FBS). Nine-point 3-fold serial dilutions of compound areadded to cells (3 ul, 1:1,000 dilution, DMSO concentration was 0.1%;final top concentration was 10 or 1 uM, depending on compounds potency)and incubated for 3 days. Cells incubated with DMSO are used as avehicle control. Cells are harvested and subjected to western blotanalysis as described above. SmD3me2s and H3R8me2s bands can bequantified by ImageJ. Signals can be normalized to β-Actin and DMSOcontrol. IC₅₀ values can be calculated using Graphpad Prism.

Cell Treatment and Western Blotting for Detecting Symmetric Di-MethylArginine (sDMA) Marks (in Granta-519 and U-87 MG Cell Lines)

Compound titration and cell culture. Compounds were dissolved in DMSO tomake 10 mM stock and 3-fold series dilutions were further conducted tomake working stocks top at 1 mM. Granta-519 cells were maintained inPRMI 1640 (Corning Cellgro, Catalog #: 10-040-CV) supplemented with 10%v/v FGS (GE Healthcare, Catalog #: SH30910.03) and U-87 MG cells weremaintained in DMEM (Corning Cellgro, Catalog #: 10-013-CV) with 10% FBSand 2 mM Glutamin (Corning Cellgro, Catalog #25005CV).

To determine enzyme inhibition IC₅₀ values in Granta-519 and U-87 MGcells using Western Blot analysis. One day before experiment, Granta-519cells were passaged to a density of 0.5×10⁶ cells/ml U-87 MG cells weretrypsinized and 4×10⁵ cells were seeded into 6-well plates and allow togrow overnight. The next day, Granta-519 cells were spun down at 1,500rpm for 4 min, resuspended in fresh medium at 0.5×10⁶ cells/ml and 3 mLof culture (1.5×10⁶ cells) were seeded into 6 well plate. Eight-point,3-fold serial dilutions of compound working stocks were added to cells(3 ul; 1:1,000 dilution, DMSO concentration was 0.1%, final topconcentration at 1 uM) and incubated for 3 days. Cells incubated withDMSO was used as a vehicle control.

Cells were harvested 3 days later, resuspended in 15 uL PBS, lysed in 4%SDS, and homogenized by passing through homogenizer column (OmegaBiotek, Catalog #: HCR003). Total protein concentrations were determinedby BCA assay (ThermoFisher Scientific, Catalog #: 23225). Lysates weremixed with 5× Laemmli buffer and boiled for 5 min. Forty ug of totalprotein was separated on SDS-PAGE gels (Bio-Rad, catalog #: 4568083,4568043), transferred to PVDF membrane, blocked with 5% dry milk(Bio-Rad, Catalog #: 1706404) in TBS with 0.1% v/v Tween 20 (TBST) for 1hour at room temperature (RT), and incubated with primary antibodies(sDMA Cell signaling, Catalog #: 13222, 1:3,000; β-Actin: sigma, Catalog#: 1:5,000) in 5% dry milk in TBST at 4° C. overnight. The next day,membranes were washed with TBST, 5×5 min, and incubated with HRPconjugated seconded antibody (GE Healthcare; Catalog #: NA934-1ML,NA931-1ML; 1:5,000) for 2 hours at RT, followed by 5×5 min washes withTBST, and incubation with ECL substrates (Bio-Rad, Catalog #: 1705061,1705062). Chemiluminescent signal was captured with Fluorchem HD2 imager(Proteinsimple). SmD3me2s bands were quantified by ImageJ Signals werenormalized to β-Actin and DMSO control. IC₅₀ values were calculatedusing Graphpad Prism ([Inhibitor] vs. normalized response—Variableslope).

sDMA in Cell Western procedure (ICW): Granta-519 cells were passaged toa density of 0.5×10⁶ cells/ml one day before experiments and allowed togrow overnight. The next day (day 0), cells were spun down at 1,500 rpmfor 4 min, resuspended in fresh medium to 0.2×10⁶ cells/ml and 100 uL ofcells were added to 384-well plates using a Multidrop Combi Dispenser(ThermoFisher). A series of 9-point, 3-fold serial dilutions ofcompounds were prepared and dispensed into wells from a 1 mM stocksolution using a TECAN digital dispenser (D300e) and the DMSO%concentration was normalized in each well to 0.1%. DMSO and 3 uM ofreference compounds were used as negative (minimum inhibition) andpositive (maximum inhibition) controls, respectively. After 3 days ofincubation, cells were first resuspended and then 80 ul of cells weretransferred to a Poly-D-lysine 384-well plate (Corning, Catalog#354663), followed by 30 minutes incubation at room temperature (RT) and5 additional hours of incubation at 37° C. Cells were then fixed with 4%paraformaldehyde (Electron Microscopy, Catalog #15710) for 30 minutes atRT and permeabilized by washing the plate 5 times with 50 ul/well ofwash buffer (1×PBS with 0.1% Triton X-100), sblocked with 30 ul/well ofOdyssey blocking buffer (Li-COR, Catalog #927-40000) for 1 hour at RTwith gentle rocking, and incubated with 20 ul/well of primary antibody(sDMA: Cell signaling, Catalog #: 13222, 1:800 in Odyssey blockingbuffer) overnight at 4° C. The following day, cells were washed 5 timeswith 50 ul/well of wash buffer, incubated with 20 ul/well of secondaryantibody (800 CW goat anti-rabbit IgG (H+L), Li-COR, Catalog #926-32211,1:500; DRAQ5 (Abcam, Catalog #ab108410), 1:1000; in Odyssey blockingbuffer) for 1 hour at RT, washed again 5 times with 50 ul/well washbuffer, followed by 1 last wash with water. The plate was left to dry atRT and scanned on Licor Odyssey CLx imaging system to acquire integratedintensities at 700 nm and 800 nm channels.

U87-MG cells were trypsinized one day before the experiment, seeded intoa 384-well plate at 2500 cells/well using a Multidrop Combi Dispenser(ThermoFisher) and allowed to grow overnight. The next day (day 0), aseries of 9-point, 3-fold serial dilutions of compounds were preparedand dispensed into wells from a 1 mM stock solution using a TECANdigital dispenser (D300e) and the DMSO% concentration was normalized to0.1%. Three days later, media was removed, and cells were processed asdescribed above.

To determine IC₅₀ values, the ratio for each well was calculated (sDMA800 nm value/DRAQ5 700 nm value). Each plate included 28 negativecontrol wells (DMSO only, minimum inhibition) and 18 positive controlwells for maximum inhibition (treating with 3 uM of a referencecompounds, background wells). The average ratios of minimum and maximuminhibition controls were calculated and used to determine the percentageof sDMA, relative to DMSO, for each well in the plate.

These procedures generated the sDMA data in Table 7.

Cell Proliferation Assay to Determine IC₅₀ in Granta-519 and U-87 MGCells Cell Proliferation Assay to Determine IC₅₀ on Granta-519Cells—Procedure 1

Granta-519 cells were maintained in PRMI 1640 (Corning Cellgro, Catalog#: 10-040-CV) medium supplemented with 10% v/v FBS (GE Healthcare,Catalog #: SH30910.03). Compounds were dissolved in DMSO to make 10 mMstocks and stored at −20° C. Nine-point, 3-fold serial dilutions weremade with DMSO with top concentration at 1 mM (working stocks).

On day of experiment, compound working stocks were further diluted at1:50 with fresh medium in 96 well plate, and 10 μL of diluted drugs wereadded to a new 96 well plate for proliferation assay. Cells growing atexponential phase were spun down at 1500 rpm for 4 min and resuspend infresh medium to reach a density of 0.5×10⁶ cells/mL 200 ul of cells wereadded to 96 well plate containing diluted drugs and incubated for 3days. DMSO was used a vehicle control.

On day 3, 10 μL of Cell Counting Kit-8 (CCK-8, Jojindo, CK-04-13)solution was added to a new 96 well plate. Cells incubated with drugsfor 3 days were resuspended by pipetting up and down, and 100 μL ofcells were transferred to 96 well plate containing CCK-8 reagent tomeasure viable cells. Plates were incubated in CO2 incubator for 2 hoursand OD450 values were measured with a microplate reader (iMarkmicroplate reader, Bio-Rad).

For re-plating, compound working stocks were diluted at 1:50 with freshmedium and 10 μL of diluted drugs were added to a new 96 well plate.Cells from Day 3 plate (50 ul) were added to 96 well plate containingfresh drug and additional 150 μL of fresh medium was added to reach 200μL volume. Plate was returned to CO₂ incubator and incubated for 3 moredays. Viable cells measurement and re-plating were repeated on day 6,and the final viable cells measurement was taken on day 10.

Percentage of viable cells, relative to DMSO vehicle control, werecalculated and plotted in Graphpad Prism ([Inhibitor] vs. normalizedresponse—Variable slope) to determine proliferation IC₅₀ values on day10.

Cell Proliferation Assay to Determine IC₅₀ in Granta-519 and U-87 MGCells—Procedure 2

One day before experiment, Granta-519 cells were passaged to a densityof 0.5×10⁶ cells/ml. U-87 MG cells were trypsinized and 2,000 cells wereseeded into 96-well plates and allow to grow overnight. On the day ofexperiment (day 0), Granta-519 Cells were spun down at 1,500 rpm for 4min, resuspended in fresh medium to 0.5×10⁶ cells/ml and 190 ul of cellswere added to 96 wells plates. For U-87 MG cells, old medium was removedand replaced with 190 uL fresh medium. Compound working stocks werefirst diluted at 1:50 with fresh medium in 96 well plate and 10 μL ofdiluted drugs were added to 96 well plates containing cells andincubated for 3 days. DMSO was used a vehicle control.

One day 3, 50 uL of Granta-519 cells were transferred to a new 96-wellplate and 140 uL fresh medium was added. For U-87 MG cells, old mediumwas removed and replaced with 190 uL fresh medium. Compound workingstocks were freshly diluted at 1:50 with medium and 10 μL of diluteddrugs were added to cells and grow for 3 additional days. The sameprocess was repeated on day 6. Cells were allowed to grow for additional4 days.

On day 10, 100 uL Granta-519 cells were transferred to a new 96 wellplate and 10 μL of Cell Counting Kit-8 (CCK-8, Jojindo, CK-04-13)solution was added. For U-87 MG cells, old medium was removed andreplaced with 100 uL fresh medium and 10 uL CCK-8 solution was added.Plates were incubated in CO₂ incubator for 2 hours (Granta-519 cells) or30 min (U-87 MG cells) and OD₄₅₀ values were measured with a microplatereader (iMark microplate reader, Bio-Rad). Percentage of viable cells,relative to DMSO vehicle control, were calculated and plotted inGraphpad Prism ([Inhibitor] vs. normalized response—Variable slope) todetermine proliferation IC₅₀ values on day 10.

These cell proliferation procedures produced the data in Table 7.

TABLE 7 Biochemical and cellular potency (in Granta-519 and U87 MG cellline) * Flash Ex. Plate HotSpot sDMA_Granta Prolif_Granta sDMA_U87Prolif_U87 No IC₅₀ μM N IC₅₀ μM N IC₅₀ μM N IC₅₀ μM N IC₅₀ μM N IC₅₀ μMN 1 0.0062 4 0.003 1 0.022 3 0.038 2 2 0.0041 3 0.002 1 0.02 2 0.035 1 60.0028 2 0.0007 1 0.038 2 0.067 2 0.094 1 0.115 1 9 0.0243 2 0.005 20.11 1 0.388 1 11 0.0068 14 0.003 1 0.033 2 0.092 2 0.053 2 0.206 2 140.0044 1 0.006 2 0.203 1 20 0.121 1 0.032 1 21 0.148 1 0.153 1 22 0.1891 0.057 1 23 0.697 1 35 0.287 1 0.046 1 36 0.02 1 0.011 1 3.78 1 1.1 137 0.031 1 0.012 1 38 0.221 1 0.368 1 39 1.24 1 40 1.03 1 41 0.23 1 420.392 1 43 0.181 1 44 0.0237 1 0.113 1 1.16 1 45 0.0066 1 0.054 1 0.5471 46 2.06 1 47 0.274 1 48 0.074 1 0.337 1 0.758 2 10 1 49 0.078 1 0.3751 0.625 2 10 1 50 2.52 1 51 0.051 1 52 0.0093 1 0.009 1 1.7 1 0.396 1 530.134 1 0.164 1 5.24 2 10 1 54 0.0376 1 0.759 1 1.01 1 55 0.2 1 560.0176 1 0.923 1 50 1 * Initial testing of Example 1 gave an IC₅₀ of0.0063 μM (N = 3; flash plate); sDMS (Granta) IC₅₀ of 0.009 μM (N = 1),and Prolif_(Granta) IC₅₀ uM of 0.028 (N = 1). Initial testing of Example2 gave an IC₅₀ of 0.0042 μM (N = 1; flash plate). Initial testing ofExample 11 gave an IC₅₀ of 0.0059 μM (N = 1; flash plate).

In Vivo Pharmacokinetic Properties of Example 1, 6 and 11.

In a rat (SD, male, non-fasted) non-crossover cassette (n=2) PK study,Example 1 was dosed at 0.5 mg/kg (DMA: 20% HPBCD=5/95, solution) withanother compound via i.v. administration (N=3) and 2 mg/kg (0.5% NaCMC+0.5% Tween80, suspension) with another compound via oral gauge(p.o.) (N=3). It showed average T_(1/2) of 0.35 hr. Vss of 1.36 L/kg,blood clearance of 56.2 mL/min/kg in the i.v. group; it showed averagedose normalized AUC of 145 ng*h*kg/mL/mg and 48% of oral bioavailabilityin the p.o. group.

In a rat (SD, male and female, non-fasted) non-crossover cassette (n=4)PK study. Example 6 was dosed at 0.2 mg/kg (DMA: 20% HPBCD=5:95,solution) with other 3 compounds via i.v. administration (N=2 per sex)and 2 mg/kg (0.5% Na CMC+0.5% Tween80, suspension) with other 3compounds via oral gauge (p.o.) (N=2 per sex). It showed average T_(1/2)of 0.46 hr, Vss of 1.81 L/kg, blood clearance of 59.2 mL/min/kg in thei.v. male group. It showed average T_(1/2) of 1.69 hr, Vss of 1.91 L/kg,blood clearance of 21.6 mL/min/kg in the i.v. female group, it showedaverage dose normalized AUC of 144 ng*h*kg/mL/mg and 51.1% of oralbioavailability in the male p.o. group; it showed average dosenormalized AUC of 1143 ng*h*kg/mL/mg and >100% of oral bioavailabilityin the female p.o. group.

In a rat (SD, male and female, non-fasted) non-crossover PK study,Example 11 was dosed at 1 mg/kg (DMA: 20% HPBCD=5.95, solution) via i.v.administration (N=3 per sex) and 3 mg/kg (0.5% Na CMC+0.5% Tween80,suspension) via oral gauge (p.o.) (N=3 per sex). It showed averageT_(1/2) of 1.06 hr, Vss of 2.85 L/kg, blood clearance of 77.5 mL/min/kgin the i.v. male group; It showed average T_(1/2) of 1.84 hr, Vss of2.71 L/kg, blood clearance of 37.2 mL/min/kg in the i.v. female group;it showed average dose normalized AUC of 33 ng*h*kg/mL/mg and 13% oforal bioavailability in the male p.o. group; it showed average dosenormalized AUC of 434 ng*h*kg/mL/mg and 97% of oral bioavailability inthe female p.o. group.

In Vivo Brain Exposure of Example 2, 6 and 11.

In a mouse (CD-1, male) brain exposure cassette study, Examples 2 and 6were dosed together at 10 mg/kg each (0.5% Na CMC+0.5% Tween80,solution) via oral gauge (p.o.). At 3 time points (N=3), 2 h, 4 h and 8h, plasma and brain samples were analyzed for average drugconcentrations.

Plasma—2 h Plasma—4 h Plasma—8 h Brain—2 h Brain—4 h Brain—8 h CMPDng/mL ng/mL ng/mL ng/g ng/g ng/g Ex. 2 1610 802 178 244 174 76.2 Ex. 6380 138 33.7 183 45.9 50.5

In a mouse (CD-1, male) brain exposure study, Examples 11 was dosed at10 mg/kg each (0.5% Na CMC+0.5% Tween80, solution) via oral gauge(p.o.). At 3 times points (N=3), 1 h, 2 h and 4 h, plasma and brainsamples were analyzed for average drug concentrations.

Plasma—1 h Plasma—2 h Plasma—4 h Brain—1 h Brain—2 h Brain—4 h CMPDng/mL ng/mL ng/mL ng/g ng/g ng/g Ex. 11 207 148 53.6 188 85.7 50.2

In Vivo Tumor Growth Inhibition of Example 1 in Granta-519 MouseXenograft Model.

Granta-519 cells was maintained in DMEM medium supplemented with 10%fetal bovine serum and 2 mM L-Glutamine at 37° C. in an atmosphere of 5%CO₂ in air. Cells in exponential growth phase were harvested and 1×10⁷cells in 0.1 mL of PBS with Matrigel (1:1) were injected subcutaneouslyat the right lower flank region of each mouse for tumor development. Thetreatments were started when the mean tumor size reaches approximately300-400 mm³. Mice were assigned into groups using StudyDirector™software (Studylog Systems, Inc. CA, USA) and one optimal randomizationdesign (generated by either Matched distribution or Stratified method)that shows minimal group to group variation in tumor volume was selectedfor group allocation. Example 1 or vehicle (0.5% Na CMC+0.5% Tween80,suspension) were administered orally (BID or QD for Example 1, QD forvehicle) at a dose of 25 mg/kg BID and 50 mg/kg QD for 16 and 20 days,respectively. Body weights and tumor size were measured every 3 or 4days after randomization. Animals were euthanized 12 hours after lastdosing, and blood and tumor samples were collected for analysis.

Following this protocol, Example 1 showed an average of 76.7% (N=5)tumor growth inhibition at 25 mg/kg BID with body weight loss of 6.75%,an average of 5.8% tumor growth inhibition at 50 mg/kg QD with bodyweight gain of 10.1%.

In Vivo Tumor Growth Inhibition of Example 11 in U87 MG Mouse OrthotopicModel.

U87MG-luc3 human glioblastoma cells were grown to mid-log phase inEagle's Minimum Essential Medium containing 10% fetal bovine serum, 2 mMglutamine, 1× non-essential amino acids, 0.075% sodium bicarbonate, 1 mMsodium pyruvate, 100 units/mL sodium penicillin G, 25 μg/mL gentamicin,and 100 μg/mL streptomycin sulfate. The tumor cells were cultured intissue culture flasks in a humidified incubator at 37° C., in anatmosphere of 5% CO₂ and 95% air. Cells were cultured in 2 μg/mLpuromycin until the second to last passage before implant, grown tomid-log phase and harvested. Post-implant verification ofluciferase-expressing cells was performed by maintaining cells inculture for three passages after implant to ensure stable doubling time.Limiting dilution was used to verify and quantitate light production inthe presence of luciferin. Cells were harvested at mid-log phase andresuspended at a concentration of 1×10⁸ cells/mL in PBS. Each mouse(Female athymic nude mice (Crl:NU(NCr)-Foxn/nm, Charles River)) receivedan intracranial injection of 1×10⁶ U87MG-luc3 cells (0.01 mL cellsuspension) and tumor growth was monitored through whole bodybioluminescent imaging. Four days post cell implant, designated as Day 1of the study, the animals were sorted into five groups based on fluxvalues before treatment starts. Ex. 11 or vehicle (0.5% Na CMC+0.5%Tween80) was administered orally BID. Ex. 11 was dosed at 10, 20 mg/kgBID and 50 mg/kg BID, 7-day or/7-day off for 22 days. Animals werecontinued to be observed to obtain overall survival data.

In Vivo bioluminescence images (dorsal were captured to monitor tumorprogression. Luciferase activity was measured in live animals using IVISSpectrum CT (Perkin Elmer, MA) equipped with a CCD camera (cooled at−90° C.), mounted on a light-tight specimen chamber. Regions of interestwere drawn around each mouse image, and flux was quantified and reportedas 10⁶ photons per second (p/s). For overall survival, animals weremonitored individually to an endpoint of moribundity due to progressionof systemic lymphoma. Full hind limb paralysis, severe ocular proptosisor moribundity all called for euthanasia.

Ex. 11 showed an average (N=6-8) of 10%, 61%, and 85% of tumor growthinhibition at 10, 20, and 50 (7-day on/7-day off) mg/kg BID on day 29.The median survival for vehicle and the three treated groups are 31.5,41, 37.5, and 39 days, respectively.

The present disclosure is also directed to the following aspects:

-   Aspect 1. A compound of Formula I or Formula II:

-   -   or a pharmaceutically acceptable salt or solvate thereof,        wherein    -   A is N, C—H or C—R⁴ wherein R⁴ is halo;    -   R¹ is —C₁-C₆alk-fused aryl, or —C₁-C₆alk-fused heteroaryl    -   R² is halo, —C₁-C₆alkyl, —C₁-C₆alk-O—C₁-C₆alkyl, —NR⁵R⁵′,        —NHC(O)NR⁵R⁵′, —NHC(S)NR⁵R⁵′, —NH—O—R⁵, or —NH—NR⁵R⁵′;    -   R³ is H, halo, NH₂, or —C₁-C₆alkyl;    -   R⁵ and R⁵′ are each independently H, C₁-C₆alkyl, or        —C₁-C₆alk-OC₁-C₆alkyl,    -   or R⁵ and R⁵′, together with the atom to which they are        attached, form a C₂-C₆heterocycloalkyl ring; and    -   R⁶ is H or —C₁-C₆alkyl.

-   Aspect 2. The compound of aspect 1 wherein R¹ is —C₁-C₆alk-fused    aryl.

-   Aspect 3. The compound of aspect 2 wherein the fused aryl is    bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,    7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl, or    7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl.

-   Aspect 4. The compound of aspect 2 wherein R¹ is    —CH₂-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,    —CH₂-7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,    —CH₂-7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,    —CH(OH)—bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,    —CH(OH)-7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,    —CH(OH)-7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,    —CH(F)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,    —CH(F)-7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,    —CH(F)-7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,    —CH(NH₂)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,    —CH(NH₂)-7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,    —CH(NH₂)-7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,    —CH(Me)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,    —CH(Me)-7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,    —CH(Me)-7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,    —C(Me)(OH)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,    —C(Me)(OH)-7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl, or    —C(Me)(OH)-7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl.

-   Aspect 5. The compound of aspect 1 wherein R¹ is —C₁-C₆alk-fused    heteroaryl.

-   Aspect 6. The compound of aspect 5 wherein the fused heteroaryl is    2,3-dihydrobenzofuran-6-yl.

-   Aspect 7. The compound of aspect 5, wherein R¹ is    —CH₂-2,3-dihydrobenzofuran-6-yl, —CH(OH)-2,3-dihydrobenzofuran-6-yl,    —CH(F)-2,3-dihydrobenzofuran-6-yl,    —CH(NH₂)-2,3-dihydrobenzofuran-6-yl,    —CH(Me)-2,3-dihydrobenzofuran-6-yl, or    —C(Me)(OH)-2,3-dihydrobenzofuran-6-yl.

-   Aspect 8. The compound of any one of aspects 1 to 7, wherein R² is    —C₁-C₆alkyl, preferably methyl.

-   Aspect 9. The compound of any one of aspects 1 to 7, wherein R² is    —NR⁵R⁵′, and R⁵ and R⁵′ are both H.

-   Aspect 10. The compound of any one of aspects 1 to 7, wherein R² is    —NH—O—R⁵, and R⁵ is H or C₁-C₆alkyl.

-   Aspect 11. The compound of any one of aspects 1 to 7, wherein R² is    —NHC(O)NR⁵R⁵′, and R⁵ and R⁵′ are each C₁-C₆alkyl.

-   Aspect 12. The compound of any one of aspects 1 to 7, wherein R² is    —NHC(O)NR⁵R⁵′, and R⁵ and R⁵′ together with the atom to which they    are attached, form a C₂-C₆heterocycloalkyl ring.

-   Aspect 13. The compound of any one of aspects 1 to 12 wherein R³ is    H.

-   Aspect 14. The compound of any one of aspects 1 to 13, wherein A is    N.

-   Aspect 15. The compound of any one of aspects 1 to 13, wherein A is    C—R⁵ and R⁴ is H or F.

-   Aspect 16. The compound of any one of aspects 1 to 15, wherein R⁶ is    H.

-   Aspect 17. The compound of any one of aspects 1 to 15, wherein R⁴ is    —CH₃.

-   Aspect 18. The compound of any one of aspects 1 to 17, which is a    compound of Formula I.

-   Aspect 19. The compound of any one of aspects 1 to 17, which is a    compound of Formula II.

-   Aspect 20. A pharmaceutical composition comprising a compound    according to any one of aspects 1 to 19 and a pharmaceutically    acceptable excipient.

-   Aspect 21. A method of inhibiting a protein arginine    methyltransferase 5 (PRMT5) enzyme, comprising contacting the PRMT5    enzyme with an effective amount of a compound of any one of any one    of aspects 1 to 19.

-   Aspect 22. A method of treating a disease or disorder associated    with aberrant PRMT5 activity in a subject comprising administering    to the subject, a compound of any one of aspects 1 to 19.

-   Aspect 23. The method of aspect 22, wherein the disease or disorder    associated with aberrant PRMT5 activity is breast cancer, lung    cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian    cancer, uterine cancer, cervical cancer, leukemia such as acute    myeloid leukemia (AML), acute lymphocytic leukemia, chronic    lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia,    myelodysplasia, myeloproliferative disorders, acute myelogenous    leukemia (AML), chronic myelogenous leukemia (CML), mastocytosis    chronic lymphocytic leukemia (CLL), multiple myeloma (MM),    myelodysplastic syndrome (MDS), epidermoid cancer, or    hemoglobinopathies such as b-thalassemia and sickle cell disease    (SCD).

-   Aspect 24. The method of aspect 22 or aspect 23, wherein the    compound is administered in combination with one or more other    agents.

1. A compound of Formula I or Formula II:

or a pharmaceutically acceptable salt or solvate thereof; wherein A isN, C—H, C—R⁴, wherein R⁴ is halo or CF₃; R¹ is—CH(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—CH(OH)-(7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—CH(OH)-(7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—CH(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl),—CH(OH)-(7,7-dimethylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl),—CH(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-ol-3-yl),—CH(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-one-3-yl),—CH(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile-3-yl),—CH(OH)-(2,3-dihydro-1H-inden-5-yl),—CH(OH)-(2,3-dihydrobenzofuran-6-yl),—CH(OH)-(5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl),—C(Me)(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—C(Me)(OH)-(7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—C(Me)(OH)-(7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl),—C(Me)(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl),—C(Me)(OH)-(7,7-dimethylbicyclo[4.2.0]octa-1(6),2,4-triene-3-yl),—C(Me)(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-ol-3-yl),—C(Me)(OH)-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-one-3-yl),—C(Me)(OH)-(7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile-3-yl),or —C(Me)(OH)-(2,3-dihydro-1H-inden-5-yl),—C(Me)(OH)-(2,3-dihydrobenzofuran-6-yl),—C(Me)(OH)-(5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl); R² is halo,—C₁-C₆alkyl, —C₂-C₄alkenyl, —C₁-C₆alk-OH, —C₁-C₆alk-halo,—C₁-C₆alk-O—C₁-C₆alkyl, —C₁-C₆alk-O—C₁-C₆alk-aryl, —O—C₁-C₆alkyl,—NR⁵R⁵′, —NHC(O)NR⁵R⁵′, —NHC(S)NR⁵R⁵′, —NH—O—R⁵, or —NH—NR⁵R⁵′; R³ is H;R⁵ and R⁵′ are each independently H, C₁-C₆alkyl, or—C₁-C₆alk-OC₁-C₆alkyl; or R⁵ and R⁵′, together with the atom to whichthey are attached, form a C₂-C₆heterocycloalkyl ring; and R⁶ is H or—CH₃.
 2. The compound of claim 1, wherein R² is —Cl.
 3. The compound ofclaim 1, wherein R² is methyl, butyl, or isopropyl.
 4. The compound ofclaim 1, wherein R² is vinyl or isopropenyl.
 5. The compound of claim 1,wherein R² is —CH₂OH or —CH₂CH₂OH.
 6. The compound of claim 1, whereinR² is —CH₂Cl or —CH₂F.
 7. The compound of claim 1, wherein R² is—CH₂—O—CH₂CH₃ or —CH₂CH₂—O—CH₃.
 8. The compound of claim 1, wherein R²is —CH₂CH₂—O—CH₂-phenyl.
 9. The compound of claim 1, wherein R² is—OCH₃.
 10. The compound of claim 1, wherein R² is —NR⁵R⁵′, and R⁵ andR⁵′ are both H.
 11. The compound of claim 1, wherein R² is —NR⁵R⁵′, andR⁵ is methyl and R⁵′ is H.
 12. The compound of claim 1, wherein R² is—NH—O—R⁵, and R⁵ is H or C₁-C₆alkyl.
 13. The compound of claim 1,wherein R² is —NHC(0)NR⁵R⁵′, and R⁵ and R⁵′ are each —C₁-C₆alkyl. 14.The compound of claim 1, wherein R² is —NHC(O)NR⁵R⁵′, and R⁵ and R⁵′together with the atom to which they are attached, form aC₂-C₆heterocycloalkyl ring.
 15. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein the compound is:(2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-1-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-1-hydroxyethyl)tetrahydrofuran-3,4-diol;(2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)tetrahydrofuran-3,4-diol;(2R,3R,4S,5S)-2-(6-amino-9H-purin-9-yl)-5-((R)-1-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-1-hydroxyethyl)tetrahydrofuran-3,4-diol;(2R,3R,4S,5S)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-1-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-1-hydroxyethyl)tetrahydrofuran-3,4-diol;(2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)tetrahydrofuran-3,4-diol;(2R,3R,4S,5R)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)tetrahydrofuran-3,4-diol;(2S,3S,4R,5R)-2-((R)-1-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-1-hydroxyethyl)-5-(6-methyl-9H-purin-9-yl)tetrahydrofuran-3,4-diol;(2S,3 S,4R,5R)-2-((R)-1-(bicyclo[4.2.0]octa- 1(6),2,4-trien-3-yl)-1-hydroxyethyl)-5-(5-fluoro-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;(2 S,3 S,4R,5R)-2-((R)-1-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-1-hydroxyethyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;(2R,3S,4R,5R)-2-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-5-(6-methyl-9H-purin-9-yl)tetrahydrofuran-3,4-diol;(2R,3S,4R,5R)-2-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;(2R,3S,4R,5R)-2-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-5-(5-fluoro-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;(2R,3 S,4R,5R)-2-((R)-(2,3-dihydrobenzofuran-6-yl)(hydroxy)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;(2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-(2,3-dihydrobenzofuran-6-yl)(hydroxy)methyl)tetrahydrofuran-3,4-diol;(2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((1R)-(7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)(hydroxy)methyl)tetrahydrofuran-3,4-diol; (2R,3S,4R,5R)-2-((1R)-(7-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)(hydroxy)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;(2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-(7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)(hydroxy)methyl)tetrahydrofuran-3,4-diol;(2R,3S,4R,5R)-2-((R)-(7,7-difluorobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)(hydroxy)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;(2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-3-methyltetrahydrofuran-3,4-diol;7-((2R,3R,4 S,5R)-5-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-oneO-methyl oxime; 7-((2R,3R,4 S,5R)-5-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-oneO-ethyl oxime; 7-((2R,3R,4 S,5S)-5-((R)-1-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-1-hydroxyethyl)-3,4-dihydroxytetrahydrofuran-2-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-oneO-ethyl oxime;3-(7-((2R,3R,4S,5R)-5-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,1-dimethylurea;N-(7-((2R,3R,4S,5R)-5-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxamide;(1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((S)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)cyclopentane-1,2-diol;(1R,2S,3R,5S)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((S)-1-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-1-hydroxyethyl)cyclopentane-1,2-diol;3-(7-((1R,2S,3R,4R)-4-((S)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-2,3-dihydroxycyclopentyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,1-dimethylurea;N-(7-((1R,2S,3R,4R)-4-((S)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-2,3-dihydroxycyclopentyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxamide;3-(7-((1R,2S,3R,4S)-4-((S)-1-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-1-hydroxyethyl)-2,3-dihydroxycyclopentyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,1-dimethylurea;(2R,3 S,4R, 5R)-2-((1R)-hydroxy(7-methylbicyclo[4.2.0] octa-1(6),2,4-trien-3-yl)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;3-((R)-((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-2-yl)(hydroxy)methyl)bicyclo[4.2.0]octa-1(6),2,4-trien-7-one;(2R,3 S,4R, 5R)-2-((1R)-hydroxy(7-hydroxybicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;(2R,3S,4R,5R)-2-((R)-(7,7-dimethylbicyclo[4.2 0]octa-1(6),2,4-trien-3-yl)(hydroxy)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;3-((R)-((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-2-yl)(hydroxy)methyl)-7-methylbicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonitrile;(2R,3S,4R,5R)-2-[(R)-4-bicyclo[4.2.0]octa-1,3,5-trienyl(hydroxy)methyl]-5-(4-methoxypyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;(2R,3R,4S,5R)-2-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-bicyclo[4.2.0]octa-1,3,5-trien-3-yl(hydroxy)methyl)tetrahydrofuran-3,4-diol;(2R,3R,4S,5R)-2-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)tetrahydrofuran-3,4-diol;(2R,3R,4S,5R)-2-(4-amino-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)tetrahydrofuran-3,4-diol;(2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((S)-1-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-1-hydroxyethyl)tetrahydrofuran-3,4-diol;(2R,3S,4R,5R)-2-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-5-(4-(prop-1-en-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;(2R,3S,4R,5R)-2-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-5-(4-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;(2R,3S,4R,5R)-2-((R)-bicyclo[4.2.0]octa-1,3,5-trien-3-yl(hydroxy)methyl)-5-(4-butyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;(2R,3S,4R,5R)-2-((R)-bicyclo[4.2.0]octa-1,3,5-trien-3-yl(hydroxy)methyl)-5-(4-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;(2R,3S,4R,5R)-2-((R)-(2,3-dihydro-1H-inden-5-yl)(hydroxy)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;(2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-(2,3-dihydro-1H-inden-5-yl)(hydroxy)methyl)tetrahydrofuran-3,4-diol;(2R,3S,4R,5R)-2-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-5-(4-vinyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;(2R,3S,4R,5R)-2-((S)-bicyclo[4.2.0]octa-1,3,5-trien-3-yl(hydroxy)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;(2R,3S,4R,5R)-2-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-5-(4-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;(2R,3S,4R,5R)-2-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-5-(4-(fluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;(2R,3S,4R,5R)-2-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-5-(4-(ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;(2R,3S,4R,5R)-2-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-5-(4-(chloromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;(2S,3S,4R,5R)-2-((S)-(5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl)(hydroxy)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;(2R,3S,4R,5R)-2-((R)-bicyclo[4.2.0]octa-1,3,5-trien-3-yl(hydroxy)methyl)-5-(4-(2-hydroxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;(2R,3S,4R,5R)-2-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-5-(4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol;(2R,3R,4S,5R)-2-(4-(2-(benzyloxy)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)tetrahydrofuran-3,4-diol;or(2R,3S,4R,5R)-2-((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl(hydroxy)methyl)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol.16. A pharmaceutical composition comprising a compound according toclaim 1 and a pharmaceutically acceptable excipient.
 17. A method ofinhibiting a protein arginine methyltransferase 5 (PRMT5) enzyme,comprising: contacting the PRMT5 enzyme with an effective amount of acompound of claim
 1. 18. A method of treating a disease or disorderassociated with aberrant PRMT5 activity in a subject comprisingadministering to the subject, a compound of claim
 1. 19. The method ofclaim 18, wherein the disease or disorder associated with aberrant PRMT5activity is breast cancer, lung cancer, pancreatic cancer, prostatecancer, colon cancer, ovarian cancer, uterine cancer, cervical cancer,leukemia such as acute myeloid leukemia (AML), acute lymphocyticleukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairycell leukemia, myelodysplasia, myeloproliferative disorders, acutemyelogenous leukemia (AML), chronic myelogenous leukemia (CML),mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM),myelodysplastic syndrome (MDS), epidermoid cancer, or hemoglobinopathiessuch as b-thalassemia and sickle cell disease (SCD); CDKN2A deletedcancers; 9P deleted cancers; MTAP deleted cancers; glioblastomamultiforme (GBM), NSCLC, head and neck cancer, bladder cancer, orhepatocellular carcinoma.
 20. The method of claim 19, wherein thecompound is administered in combination with one or more other agents.